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Professor Bertrand Oubier
A French archeologist suspected of having murdered his wife, Carol Kleimachs. He is used by Karzac in financing the drug smuggling. In Karzac's boat, Oubier heard the truth about the real suspect and then shot by Karzac.
- Implausible Deniability: He claims that he never went to Quaramonte but instead he goes to London to deal with Karzac.
- Last-Name Basis: His name is rarely mentioned in the whole game.
- The Mourning After: Although his wife was a mean person, the professor still loves her.
- Unwitting Pawn: Used by Karzac to get the information about the three stones.
- You Have Outlived Your Usefulness: He is killed in London after he finds out that his wife was killed by Karzac.
Karzac
A suspected drug smuggler with a short temper. Karzac plans to revive Tezcatlipoca as well as to eliminate the three spirit stones. He kills Oubier's wife and then used Oubier to finance the drug smuggling operation. At the start of the game, he organises Nico's abduction to get the Coyote Stone back.
- Big Bad: Of The Smoking Mirror.
- Deal with the Devil: To Tezcatlipoca who promised to give power to Karzac if he is released from obsidian mirror.
- Hair-Trigger Temper: In the prologue comic of The Smoking Mirror, he shoots one of his men after he finds out that Nico stole an important artifact.
- Hoist by His Own Petard: Near the end of the game, he's killed by Tezcatlipoca after he summons it.
- Karmic Death: He killed Oubier because the latter had outlived his usefulness. When he frees Tezcatlipoca, the god does the same thing to him.
- Psychotic Smirk: At the climax of the game, his smile is reflected in the obsidian mirror after he finishes his ceremony.
- Stripped to the Bone: Quickly reduced to a skeleton upon being impaled by Tezcatlipoca
- Talking in Your Dreams: He tells Oubier that he met Tezcatlipoca in his dreams and talked about ruling the world.
- You Have Outlived Your Usefulness: In the final cutscene, the first thing Tezcatlipoca does after being set free is killing Karzac, the same person that released him.
Pablo
Karzac's main henchman. He poses as Oubier's butler and captures Nico and leaves George to die at the burning building.
- Stripped to the Bone: He died from the bright wave unleashed from the temple while trying to escape.
Titipoco
A dwarf who barely speaks English and one of Karzac's henchmen. He knocks Nico unconscious with a blow dart at the beginning of the game.
- Ambiguously Brown: His name can vaguely resemble one from a Central American language, and, considering the main section of the game happens in a Latin American Banana Republic, he may as well hail from there.
- Heel–Face Turn: He's saved by George in Marseilles and later he assists George and Nico to stop Karzac's plans.
- I Owe You My Life: He is grateful for being saved by George, which is why he decides to help the heroes to stop Karzac.
- Tranquillizer Dart: He shoots Nico's neck at the start of the game.
- The Unintelligible: His only spoken dialogues are grunts and some Spanish words, but he seems to understand what George and Nico say.
General Raoul Grasiento
A tall, blonde man who is the only son of a dictator in Quaramonte City.
- All Men Are Perverts: He's interested to receive Nico's panties from George.
- Calling the Old Man Out: Raoul takes a stand against his mother at the end.
- Catchphrase: "Fabuloso!"
- Chest of Medals: He has a lot of them but they're on the wrong side according to George.
- Disappeared Dad: His father is never mentioned in the game.
- Heel–Face Turn: Towards the end of the game, Raoul is convinced by Nico that Karzac plans to dispose of him after Tezcatlipoca is freed. Later, Raoul chooses Titipoco, letting his mother fall to her death.
- I Kiss Your Hand: He managed to kiss Nico's hand as a greeting. However, Nico shakes her hand in disgust.
- Nominal Hero: He gets convinced by Nico that his mother is plotting with Karzac and helps the heroes during the climax.
- Perpetual Smiler
- Phony Veteran: Pretends to be a soldier, but never fought in his life.
- Redemption Earns Life: He chooses to help Nico, George and Titipoco during the climactic battle and is the only main antagonist of the game that is still alive at the end.
- What Happened to the Mouse?: After the heroes seal Tezcatlipoca, he's not seen coming out of the pyramid in the final scene. However, given the fact that he saved Titipoco, it's unlikely that they left without him. He probably came out and went back to Quaramonte.
Madame La Presidenta Grasiento
The dictator of Quaramonte City and the mother of General Raoul.
- Corrupt Politician: She's a dictator who gets involved with Karzac's evil plans.
- Disney Villain Death: Her son doesn't save her and chooses Titipoco instead.
- Everyone Calls Him "Barkeep": Many people in Quaramonte City call her "Madam La Presidenta".
- Evil Matriarch: She detests her son for being a weak and cowardly man.
- Good Smoking, Evil Smoking: She has a picture of herself smoking.
- I Want Grandkids: The reason why she forces her son to proposal to Nico.
- Villain with Good Publicity: She has a good reputation in Quaramonte City.
Tezcatlipoca
A evil deity in South America who wants sacrifices of blood. Hundreds of years ago, he was trapped in an obsidian mirror by Quetzacoatl's loyal priests.
- Accidental Misnaming: The curator in British Museum can't pronounce Tezcatlipoca's name correctly.
- Body Horror: His body is full of torn flesh and his ribs are poking out.
- Cutscene Boss: He's only confronted during a cutscene.
- The Dreaded: He is feared among many people in Central America.
- Evil Laugh: When he appears in Karzac's reflection.
- Greater-Scope Villain: All of Karzac's actions are aimed at setting Tezcatlipoca free after he appeared to Karzac in a dream.
- Sealed Evil in a Can: He is trapped inside the obsidian mirror for hundreds of years. He is trapped once again by George, Nico, and Titipoco using the three stones they gathered.
- Touch of Death: His spear causes Karzac's body to melt.
- Ungrateful Bastard / You Have Outlived Your Usefulness: When he kills Karzac, it’s the latter is he actually spoke to Karzac in his dreams, or the former if it was just all delusions of Karzac’s.
Mr. Glease
The owner of Glease Gallery. Despite owning a gallery in France, he prefers himself as British. George reminds Glease of an older version of André, with long ponytail and terrible attitude.
- Identical Stranger: Glease has a similar appearance to André, from his haughty facial expression to his ponytail. The biggest difference is the age and the fact Glease is British instead of French.
- Third-Person Person: Suffers a case of illeism where one prefers to refer to oneself in third person.
Miguel
A musician who is arrested for playing traditional Quaramontean music. He is suspected of being an anti-government agent and thus sentenced to death. When Miguel is released with the help of Duane, he assists George and Nico by offering a ride on a boat to reach the pyramid in Teoculcan.
- Driven to Suicide: He thinks about hanging himself, but is stopped by George.
Conchita Garcia
The owner of a mining company. She believes that her mining site in Teoculcan was sabotaged by Oubier. She is a feminist and surrounds herself with male employees.
Renaldo
Secretary and assistant to General Grasiento. He's also a tourist guide to the pyramids in Quaramonte..
- Older Sidekick: To General Raoul Grasiento.
Father Hubert
A priest who is stranded in the jungle for eleven years and lives in a tree house. He discovers Nico and realises that she has been bitten by a poisonous river snake. He knows where to get the plant root for cure. For some reason, he refuses to go to the village.
- I'm a Man; I Can't Help It: He was affected in the Monkey Dance ritual and conceived eight children in the village.
- Lonely Piano Piece: He plays a tune on his organ in the hopes of Nico being cured.
- Robinsonade: He is trapped on the island for around 11 years. He made a tree house and some contraptions.
The Ketch Sisters - Mina and Frost
They are the last descendants of Captain Frederic Ketch, a pirate who stole the Eagle Stone from the Spanish. They are also the owners of Frederic Ketch Memorial Museum. They are planning to refurnish the museum with the help of Bronson.
- Badass Family: Most of the men in their family are seamen.
- Cloud Cuckoo Lander: Mina
- Freudian Excuse: If you adhere to the theory that their niece Emily (who was their last family member) is dead, their mild craziness and their hostility towards Rio becomes a lot harsher.
- Girlish Pigtails: Mina again.
- Insistent Terminology: Mina insists on calling her ancestor Frederic Ketch a Privateer and not a pirate.
- Jerk with a Heart of Gold: Frost may be a jerk but she defends Mina when Bronson calls Mina "crazy" and starts poking him using an umbrella.
- Kindhearted Cat Lover: They have a cat named Ruddles.
- Red Oni, Blue Oni: Red is for Mina while blue is for Frost judging by their clothes.
Emily Ketch
The niece of Ketch sisters. She is a jolly and curious girl who asks a lot of questions. Emily was taken care of by her aunt Frost and Mina as guardians after her parents died in typhoon. She's good friends with Rio, but her aunts don't like him.
- Childhood Friends: With Rio.
- Dead All Along: While not explicitly said, it's highly implied that she's already dead. This explains why everyone seemed unpleasant and baffled when George mentions her. However, for some reason, her cross is still tangible.
- Innocent Blue Eyes: Her eyes are similar to Captain Ketch's, according to George.
- Parental Abandonment: Her parents were killed by typhoon many years ago.
Captain Frederic Ketch
Frederic Ketch was a pirate who got hold of the Jaguar stone when seizing a Spanish ship. He later became a successful Privateer but was hanged by the British governor and his men who wanted to obtain Ketch's vast fortune.
- Posthumous Character: We learn about Ketch's story through his descendants Mina and Frost.
- Pirate Booty: Ketch stored his treasure chest in a cave by the beach.
- Privateer: It is said that Ketch retired from a life of piracy and became a successful privateer, gaining great wealth.
Rio
A young fisher boy that George meets in Ketch's Landing. He's a friend of Emily.
- Annoying Younger Sibling: His sister complains that Rio always gets a puffer fish for dinner.
- Childhood Friends: With Emily
- Improbable Age: George thinks that Rio is qualified being a beach bum.
- The Prankster: He once put a fish in Bronson's sleeping bag.
Bronson
A land developer hired by the Ketch sisters to refurnish the museum.
- Jerkass: He plans to replace the museum with a five-star hotel.
Carlton Hawks
A former mailman turned director. He is a director of a film adaptation of Treasure Island.
- Hawaiian-Shirted Tourist: Subverted. He's a director who wears summer-themed clothes.
Haiku McEwan
He is a teen star who plays as Jimbo Hawkins for the film-adaptation of Treasure Island.
- Embarrassing Middle Name: Averted. Haiku's middle name is "Limerick" but he doesn't mind.
- Line-of-Sight Name: He is named after a Japanese poem that his mother read.
Sharon Kowalski
The female lead of Treasure Island.
- Buxom Beauty Standard: Discussed subtly during the shoot. George comments on her amazing cleavage, Hawks commends her "heavy breathing", and confirms with cameraman Flash if he got a good shot of said breathing. Flash then jokes they should've shot the film in 3D.
- The Cameo: Her poster appears at Henri's office in The Serpent's Curse.
- Dumb Blonde: Sharon is not aware that the novel was published a long time ago.
- Fainting: Sharon is freaked out when she sees hornets chasing Bert.
Bert Savage
A muscle-bound British who is Haiku's stunt double. He had a lot of experience as a stuntman in film industry. He previously worked as a soldier.
- The Big Guy: He's a stuntman even though Haiku is smaller than him.
- Butt-Monkey: Bert admits to George that he's sick of getting into danger.
- Does Not Like Spam: He hates maple syrup.
- Trademark Favorite Food: Bert likes to eat pancakes.
- Verbal Tic: He often adds the word "flippin" when he's talking about his experience.
Flash
The only cameraman of Treasure Island.