General Timothy Treister: I may be a crazy old SOB, but I ain't no shortbuser. I know there ain't no such things as hulks.
Gathers: Oh, well, that's not all sir, Cardholder and Doe are...
Treister: Double agents angling to take over the OSI? Yep, know that too. Hell, son, I invented the secret keeping business...
- Dr. Henry Killinger, a cross between Mary Poppins and Henry Kissinger, is a supervillain life coach. First appearing to fix up the Monarch's organization and reconciling the Monarch and Dr. Girlfriend, he also tries to reconcile Rusty Venture and his ex, Myra. Failing at the latter task, Killinger still ends up saving Rusty's children so he considers the result a net positive. Returning in season 3 to help Rusty realize his potential as a supervillain, Rusty realizes Killinger's point and signs a severance package, though left completely shaken from the experience. Thanking him for his time and leaving, Killinger returns in season 6, first remaking the ineffectual Revenge Society into a truly fearsome villain team, then engaging in an epic four-way battle between himself, Phantom Limb, the Sovereign and the Investors, ending with him completely in the win and remaking a new Council of 13 and Guild in his own image, departing content with the result.
- The Sovereign is an unnamed shape shifter who took on the guise of David Bowie to lead the Guild of Calamitous Intent for decades. Despite being given the Guild by the Investors, he more than earned his position. He frames the Guild's rival villains SPHINX for the death of Jonas Venture thus ensuring their destruction in a series of brutal wars with the OSI, while also bringing about the Guild's rise to power. Would-be usurper Phantom Limb is also handily defeated twice, first by faking his death and ambushing Limb and then later giving the Guild to its true successor, Dean Venture, only to be officially given control right back. His greatest scheme involved masterminding the destruction of the Gargantua-2 space station to ensure the deaths of all his enemies, such as the Investors, Limb's Revenge Society, and the OSI, despite knowing thousands of innocents would die as well. A nobody wanting to be somebody, the ever affable Sovereign's eventual downfall is seen in a somber light despite his atrocities.
- Red Death is an infamous veteran in the supervillain community who perfectly balances his family life with his profession. Early in life, he fully embraced his darker side by indulging in wanton violence and helped to organize what would become the Movie Night Massacre aboard Jonas Venture's space, but later chooses to repress his violent side by becoming a loving father and husband and classy respectable villain. After the Monarch pretends to kidnap his family to stop him arching Dr. Venture, Red Death easily tracks him down and only stops from brutally killing him when he finds out his wife and daughter are safe. The first to piece together the Monarch is the vigilante Blue Morpho, Red Death sells him out for a place on the Council of Thirteen and later blackmails Mrs Monarch to ensure his new position. As a new councilman, Red Death and Mrs Monarch meet with a boorish and misogynistic member of a rival organization and uses his last arching rights to tie the thug to a railroad, bemoan the death of classical supervillainy, and fly off into the night cackling maniacally.
- Copycat is a supervillain from New York known publicly for his suave lingo and love of tailored suits, yet less known for also using his duplication power to further his ambitions to be the top villain in the Big Apple. First introduced meeting new councilor Mrs. Monarch at a party, Copycat publicly humiliates both her and the Monarch by luring the latter to his apartment, knocking him out with his own sleep darts, and dressing in his costume to illegally arch Dr. Venture. Using a copy still at the party, Copycat directs the rest of the council to look at the sight and severely weaken both the couple's marriage and positions in the Guild. In his final appearance, Copycat masterminds a heist of Ventech Tower and fully utilizes his team's powers to flawlessly pull off the heist until he intentionally betrays them and makes off with the valuable tech himself. After a miraculous shot causes his helicopter to crash into his apartment, Copycat simply sits back, downs a martini, and calmly accepts death.
- Molotov Cocktease is a professional mercenary assassin and the love interest and primary rival of Brock Samson. First seen rescuing Brock from a death trap, she helps him rescue the Ventures only to immediately bail to accomplish her real mission of stealing a rare panda for the Sovereign. Her greatest showing, however, was ordering Brock's old mentor Hunter Gathers to make him believe the OSI wanted him dead, hiring assassins herself to kill him, and sitting back as Brock defeated said assassins ensuring her new Black Hearts organization had no competition. Realizing Brock had gone soft in her eyes, she infiltrated his new team to rescue her new lover Monstroso and set her assassins to murder his loved ones to escape, only to later betray Monstroso to the OSI and take her place as a double agent in their employ. Despite having no henchmen or magical abilities, Molotov always manages to use her sharp mind and skills of seduction to remain in a position of power and prestige.
- General Timothy Treister is the founder and leader of the OSI, the Office of Secret Intelligence, and far more cunning than his initial insane antics would have you believe. Leading the OSI to a brutal victory in the Pyramid Wars against the villainous SPHINX, Treister would lead well into his final years despite multiple heart attacks and terminal prostate cancer. Later shown utterly destroying the Monarch's forces to rescue Brock, Treister would soon begin his master plan to ensure both his future and that of the OSI. To weed out the Guild's moles, Treister began acting like a senile old man who thought he was a Hulk, while also planting his own moles in the new vigilante SPHINX led by Hunter Gathers. When Hunter came seeking amnesty for himself and his men, he revealed his ruse by flawlessly arresting the Guild moles, calls Hunter a worthy successor and gives him the OSI, and launches himself into to space to get aliens to cure his cancer. Later reawakened by Jonas Jr aboard his space station, Treister reveals the radiation cured his cancer and turned him into a hulk, yet nevertheless selflessly sacrifices in life to ride away the station's exploding core and save thousands of lives.
- Colonel Hunter Gathers is a veteran spy working for the OSI and the harsh yet effective mentor of Brock Sampson. Guiding Brock in his younger years, Hunter put all his efforts into uncovering the Guild as the true masterminds of the Pyramid Wars and was close enough that Guild moles had to reassign him far away to prevent his search from revealing them. Later defecting from the OSI, Hunter has a sex change operation after he himself taught his would be killer Brock to never harm women and infiltrates Molotov's Black Hearts and helps her in her scheme to free Brock from the OSI. Becoming a man again, Hunter resurrects SPHINX to take out rogue villains while also leading a shadow war against the Guild's main backers, the Investors. Capturing the villain lawyer Monstroso to negotiate amnesty with the OSI, General Treister acknowledges Hunter as a worthy successor and gives him full control. Now leader of the OSI, Hunter again works with Molotov to recapture Monstroso and further weed out the remaining Guild moles. When the Sovereign attempts the purge the Council, Hunter offers the remaining councilors pardons and uses this power to keep the weakened Guild under tighter OSI control.