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- "So are you gonna, A. Listen to some fifty grand a year pension hunter, or B. A billionaire? who even the president lets finger his wife, or C? Try and be really stupid and save those two idiot mentors of yours and have everybody in the Goddamn state crawling up your ass, A, B or C?"
- ― Devin Weston to Franklin Clinton.
At one point late in the game, Steve Haines orders Franklin Clinton to kill Trevor Philips. Later, Devin Weston orders him to kill Michael De Santa. Franklin (the player) then has to choose which of his friends he is going to kill, or if he wants to save both of them, and kill Steve and Devin.
Choice A: "Kill Trevor"
If the player chooses to kill Trevor, the mission Something Sensible begins. In this ending, Franklin agrees to eliminate Trevor. He later sets up a meeting with Trevor. Franklin begins discussing the problems they are facing, but Trevor thinks this is about Michael and laments how he had been backstabbing towards him, then Franklin pulls a gun on him, saying that he was the crazy one, not Michael, and he would most likely end up getting all three of them killed. Baffled, Trevor remarks on how he has done nothing but be truthful to Franklin, which the latter accepts but does not let down the gun. Trevor, feeling betrayed again, then drives away in his truck and Franklin then chases him on the highway. During the high-speed chase, Franklin calls Michael for help. Michael then appears with his car and destroys Trevor's truck and he gets stuck under a gasoline truck. The game gives you a decision to finish off Trevor or let Trevor die off. If you shoot the gas truck, it sets the gas trail on fire, burning him alive. The gas tank short explodes afterwords. If you don't shoot him, Michael will shoot him, causing Trevor to burn to death. Michael and Franklin reflect on their journey and go their separate ways. Michael still considers Franklin as a close friend of his, but Trevor's death has affected him deeply and says he needs time from Franklin. After the credits, the player can only choose to play as Franklin and Michael, and Trevor's cut of the Union Depository bank job is split between them.
Choice B: "Kill Michael"
If the player chooses to kill Michael, the mission The Time's Come begins. In this ending, Franklin agrees to eliminate Michael. Franklin confronts Michael wishing to discuss the situation. Michael meets Franklin and is seen taking a phone call from his wife. She told him that Tracey would be attending college to which Michael replied positively. Franklin feels the pain after hearing this, but overcomes it and talks suspiciously, causing Michael to figure out that Franklin is sent to kill him. Michael then drives away, with Franklin chasing him to the top of a tower. Michael points a gun at Franklin. Franklin fights Michael and defeats him. Michael then laments how Franklin is gonna kill him, the only person who's been decent towards him. Franklin then pushes Michael off the edge and grabs him, he starts to regret his decision, but Michael refuses to forgive him and wishes he killed him before. The game gives the player a decision to save Michael or let him go. But either way, Michael falls to his death. Franklin walks away and calls Lamar on the phone to make amends. After the credits, the player can only choose to play as Franklin and Trevor and Michael's cut of the Union Depository bank job is given to his family. Later, Trevor finds out about Michael's death, and tells Franklin to stay away from him, causing them to no longer hang with each other. Amanda also knows about this and messages Franklin, saying that she wished he rot in hell.
Choice C: Deathwish
If the player chooses "Deathwish", the mission The Third Way begins. In this ending, Franklin chooses not to kill Trevor or Michael and goes to Lester for help. Franklin and Lester, at first, seem to not have any hope of thinking of a way so both Trevor and Michael survive. But after a brainstorm, Lester comes up with a plan to avoid having to kill either Michael or Trevor. They lead the FIB and Merryweather into a trap at the foundry under the pretense of melting down the gold there from the Union Depository heist. Franklin, Michael and Trevor fight both the FIB’s strike team and Merryweather. Then they decide to kill all of their enemies. Trevor then sets out to kill Steve Haines, Michael sets out to kill Harold "Stretch" Joseph, and Franklin sets out to kill Wei Cheng. After killing Haines, Trevor kidnaps Devin Weston at his house and puts him in the trunk of a car. He drives to a secluded area, and waits for Michael and Franklin to arrive. Once the three are together, they push the car off a cliff. The car hits the ground below and explodes, killing Devin. They then go their separate ways. This is the only ending in where all three protagonists survive, leaving the player the choice to play as all three.
- Michael always receives a Psychiatric Evaluation from Dr. Friedlander after the ending of the game in ending B and C.
- For endings A and B, it is possible to attempt to spare Trevor or Michael. Not shooting Trevor will result in Michael shooting him instead, and trying to pull Michael off the silo's ledge will make him headbutt Franklin, causing him to lose his grip and fall to his death.
- For all endings, it is impossible to choose what clothing Michael and Trevor will wear. Trevor will always appear in his default outfit, except with jeans and Michael will always wear his brown leather jacket and jeans.
- However, Michael wears his gray default outfit in the beginning, but will change his outfit during Ending B.
- The player cannot play as Trevor after Ending A. Likewise, the player cannot play as Michael after Ending B.
- Franklin is the only protagonist who cannot die in any of the three endings, due to him making the choice and being the main character in all of them.
- The earnings of the final heist will vary for each character depending on the ending. If A is chosen, Michael and Franklin will receive their initial cut, but each of them will also receive half of Trevor's cut. If B is chosen then Franklin and Trevor will earn their initial cut, but will not receive Michael's cut as Lester had transferred it to his family. In ending C, each of the protagonist will receive their initial cut.