The X-Files was a nine-season Long Runner, and monsters were the show's thing. Some of these were genetic mutants who acted on predatory instincts and followed their biological needs. However, several of them crossed into the Complete Monster territory. Often these cases were surprisingly light on the paranormal stuff, making them fairly mundane and all the more frightening.
- The Cigarette Smoking Man (CSM), real name Carl Gerhard Busch, is the Arch-Enemy of FBI Agents Fox Mulder and Dana Scully and the Overarching Villain of the series. Unlike the other, more well-intentioned members of the Government Conspiracy he is part of, the CSM is nothing but a cold-hearted manipulator selling out humanity for his own protection and empowerment. Directly behind the assassinations of John F. Kennedy and Martin Luther King Jr., the CSM happily takes on any task to violently dismantle any threat to his power-hungry organization. He allows Scully to be abducted and tortuously experimented on, resulting in her being afflicted with cancer and rendered infertile, putting hundreds of thousands through similar horrors. Revealed to be the father of Mulder, the CSM makes multiple attempts on the latter's life, including trying to burn him alive and later puts him through further horrific experiments, and transforms his ex-wife and son's mother into a monstrous alien-human hybrid. With every alleged moment of humanity or interest in redemption proven to be truly hollow and self-serving, the Cigarette Smoking Man shows, time and again, just how heartless a man can be, even in a world of extraterrestrial threats.
- Cecil L'Ively, from season 1's "Fire", is a handsome, yet sadistic and remorseless Serial Killer who has the power to ignite things using his mind, using his powers to kill wealthy women. After stalking them for a while, Cecil strikes and painfully burns the women to death, but also targets the rest of their family, and therefore is not above killing their children.
- Donald "Donnie" Pfaster, from season 2's "Irresistible", is an intimidating necrophiliac Serial Killer who once worked at a funeral home, but was fired upon being discovered to have such a fetish, collecting the hair and fingers of his victims when he has killed them. When Agent Mulder and Scully investigate the murders, Donnie kidnaps Scully and prepares to torture her, barely failing to kill her because of being distracted, allowing her to escape, and getting him arrested. Returning in season 7's "Orison", he is freed by the titular vigilante Orison, who frees the prisoners so that he could kill them, thinking of it as a true punishment. Donnie escapes Orison, immediately continues his killings, and once again kidnaps Scully, having become obsessed with her after she became his only victim who had escaped.
- Phyllis Paddock, from season 2's "Die Hand Die Verletzt", is a demon who poses as a substitute teacher after being accidentally summoned; the person who summoned her happened to be an innocent little boy, who she immediately kills upon seeing, tearing out his eyes and ripping his heart out. Having once been worshipped by a cult, said cult had stopped worshipping her for unknown reasons, and to this end, Phyllis kills the stepdaughter of the cult leader by forcing her to slit her wrists and then kills the leader by having a snake eating her, and then forces the other members to commit suicide.
- Colonel Jacob Wharton, from season 2's "Fresh Bones", owns a Haitian refugee camp, but instead of taking care of the immigrants, Jacob kills them for no reason at all but his own sick amusement. Some of Jacob's victims include a former prisoner who knew voodoo named Pierre Bauvais; multiple other innocent immigrants; and even a completely innocent child who did nothing to him. He also kills his own henchmen when they try stopping him from committing his heinous crimes, and he even frames the murders of his henchmen on the aforementioned Pierre Bauvais.
- Dr. Jack Franklyn (real name: Dr. Clifford Cox) from season 4's "Sanguinarium" is a demonic doctor and a narcissistic warlock who makes human sacrifices by taking over the minds of various surgeons and having them kill patients in horrific ways (draining a patient's blood via liposuction, nearly cutting a patient's head off with a laser, and melting a patient's face off) so that he can retain his youth and looks.
- John Lee Roche from season 4's "Paper Hearts" is an utterly evil child molester and Serial Killer who killed 16 little girls. He manipulated their parents to trust him, and then came back and kidnapped the girls at night. He plays sick mind games with Agent Mulder and tries to convince him that he took his little sister Samantha (whose disappearance was not explained), even though it's not true. He manages to escape from prison during the re-opened investigation and tries to take another girl. When Mulder catches them, he nearly shoots her. He doesn't regret his deeds at all and would continue if he could.