Colonel Mortimer (Van Cleef) illegally stops a train in Tucumcari, and soon after collects a bounty of $1,000 on Guy Calloway (José Terrón). Mortimer's gunslinging skill is displayed as he easily kills him from long distance. After collecting the bounty he inquires about Red "Baby" Cavanagh (José Marco), who has a $2,000 bounty, and was last seen in White Rocks.
Mortimer is told that Cavanagh has already been targeted by Eastwood's character, who is referred to as "Manco" (meaning one-armed in Spanish —see below for an explanation). We see Manco ride into town and track down Cavanagh at a saloon playing five-card draw poker. Manco kills him and his men, and takes the bounty. Eventually, the two bounty hunters, after learning about each other from different sources, meet in El Paso and, after butting heads, decide to team up to take down Indio and his gang.
Indio's primary goal is to rob the Bank of El Paso and its disguised safe containing "almost a million dollars." Mortimer persuades a reluctant Manco to join Indio's gang during the robbery in order to "get him between two fires." Manco is offered membership in the gang after rescuing one of Indio's friends from prison.
When Indio robs the bank, he brings the gang and the money to the small border town of Agua Caliente, where Mortimer reunites with Manco. The hunchback Wild (Klaus Kinski) recognizes the Colonel from a previous encounter in which the Colonel had deliberately insulted him and forces a showdown in which he is killed by the Colonel. The Colonel then proves his worth to Indio by cracking open the safe without using explosives, but Indio states his intention to wait a month if necessary to allow the furor over the bank robbery to die down and locks the money away. Manco and the Colonel plan to steal the bank money from Indio, but the bandits catch them in the act and severely beat them. Indio's right-hand man Nino (Mario Brega), on orders from Indio, kills their guard and releases the bounty hunters. Indio informs his gang that they "got away", and sends them after the escaped bounty hunters. He intends to kill off his gang with the bounty killers while he and Nino take all the loot for themselves. However, the smarter Groggy (Luigi Pistilli) figures out what Indio is up to, and kills Nino. Before he can kill Indio, he finds that the Colonel has already removed the stolen money from where Indio had hidden it. Indio convinces Groggy to join forces with him to trap the bounty-killers. The next morning, Manco and Mortimer shoot down the gang, one by one, in the streets of the town. Standing alone, Mortimer shoots Groggy when the outlaw tries to run for it, but then has his gun shot out of his hand by Indio, who then takes out his pocketwatch and begins playing it. As the chimes nears the end, Manco suddenly appears with an identical pocketwatch, playing the same tune as Indio's, which Mortimer realizes had been taken from him earlier. As this happens, Manco holds an 1854 Jennings Rifle Company Volcanic Rifle on Indio and gives his gunbelt and pistol to Mortimer, evening the odds. "Now we start", Manco announces and sits while Mortimer and Indio face off. During the standoff, Manco looks down at the pocketwatch and sees the same picture of the woman Indio had raped. The music finishes, and Mortimer outdraws and guns down Indio.
At this juncture, Mortimer takes Indio's pocketwatch. Manco gives him back the other watch and remarks on a family resemblance; the Colonel replies, "Naturally, between brother and sister". His revenge complete, he decides to take no part of the bounty. As Manco tosses Indio's body into a wagon with the corpses of the rest of the gang and counts them by the reward for each one, he realizes he is short of the $27,000 total, and spins around to gun down Groggy who had survived and was sneaking up behind him to kill him. As he leaves, he recovers the money stolen from the Bank of El Paso, though it is not clear whether he intends to return it. He then rides off into the distance with his horse towing the wagon full of the lifeless bodies of the entire gang.
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