Patrick DeWitt’s novel The Sisters Brothers tells the story of two brothers, Eli and Charlie Sisters, who work as hired killers for The Commodore, a crime boss in Oregon City, Oregon, around the time of the California gold rush. At the beginning of the novel Charlie and Eli have just finished a job, one in which Eli lost his trusted horse. Eli waits outside as Charlie goes into the Commodore’s mansion for news of their next job. Eli’s new horse is named Tub; he received it as partial payment for their most recent killing.

Charlie exits the Commodore’s and mounts the horse he took in the last job, Nimble, which is stronger and faster than Tub. They leave the Commodore’s and go to a saloon. Sitting down with a bottle of whisky, Charlie tells Eli that he is to be the lead man on the next job. Eli doesn’t like this plan, but he goes along with it anyway. For their next job for the Commodore, Eli and Charlie are to track down and kill a gold prospector in San Francisco named Hermann Kermit Warm. The brothers are to meet the Commodore’s scout, Morris, in San Francisco. Morris will point out Warm, and the brothers will do their bloody work.

The brothers ride out for San Francisco the next morning. They come upon a man walking a horse and weeping profusely. Eli goes to him and asks him what is wrong. The man doesn’t respond but nevertheless follows Eli back to their camp. Charlie and Eli both ask the man what is the matter; the man replies that they’re "all gone." They feed the weeping man and he goes on his way.

That night Charlie and Eli make camp and go to sleep. In the morning, as he puts on his boots, Eli feels a sharp pain and realizes he has been bitten by a spider. Immediately he begins to feel feverish and weak. Eli says is able to ride, so they mount their horses and move on. A few hours later Charlie tells Eli that his head has swollen to remarkable proportions, likely from the bite. They decide to stop and find a doctor. They arrive at an encampment and solicit a man claiming to be a tooth doctor. The dentist, Watts, drains the blood from Eli’s swollen face and extracts two teeth. Before they leave, Watts gives Eli a toothbrush and toothpaste and tells him to use them everyday.

They move onward, and near daybreak they come upon an old woman in a cabin. Charlie thinks they should stop there for the night, but Eli has premonitions that the place may not be safe. Charlie overrules Eli’s suspicions, however, and they decide to stay with the old woman. When they awake, they are alone, but the woman has left a string of beads hanging across the doorway. According to Charlie, this is a gypsy’s curse which will haunt them if they pass beneath the beads. Charlie suggests exiting through the window, but Eli, who’s heavier than his brother, cannot fit. Charlie leaves and promises to return with tools to cut around the window so Eli can fit out. While Charlie is gone, Eli sees a bear approaching the tree where Tub is tied. Eli tries to shoot the bear from inside the house but cannot get a good shot. The bear starts to attack Tub, so Eli leaves the house through the doorway and kills the bear, but returns inside before Charlie gets back. Tub’s only lasting injury from the bear attack is a swollen, dead-looking eye.

Riding onward, the brothers come across a group of murdered prospectors. They eventually arrive at another town with a trading post. The brothers are outfitted by a haberdasher and Eli notes how running such a shop might be a fulfilling way to make a living were he to ever decide against hired killing. At the hotel, Eli shows Charlie his toothbrush, but Charlie is not impressed. Charlie goes out to the saloon, but Eli does not join him.

The next morning, Charlie has a bad hangover, so they decide to stay in town another day. With nothing to do, Eli befriends the woman who works in the hotel. He goes into her room and they talk about the problems of family and their dreams for the future. Charlie, Eli, and Eli’s new friend go out to watch a duel taking place in town, between a lawyer and a violent ranch hand. The lawyer is well-dressed and gentlemanly but is shot down easily. The brothers leave the hotel the next day, and Eli leaves some money for the woman working at the hotel beneath his pillow.

Riding out, they come upon a riderless horse. The horse appears to be strong and healthy, and so Eli decides he will be a suitable replacement for Tub.

The brothers arrive in a town called Jacksonville. Charlie is in the midst of chastizing Eli for his weight, telling him that the woman at the hotel was not interested sexually because she wasn’t physically attracted to him. Eli vows to eat only healthy meals henceforth, and at the restaurant in town orders a moderate portion of beef with a large portion of steamed vegetables.

The next morning Charlie is hungover again, and Eli goes out to sell Tub so he can take on the horse he found. When he gets to the horse trader, however, he has a change of heart and decides to sell the horse he found and keep Tub after all.

They ride out from town and soon come upon an abandoned camp inhabited by a starving young boy. They feed the boy, and the boy says that he will go with them to California. Eli and Charlie try to dissuade him, but the boy is adamant. They ride away swiftly, leaving the boy in their dust.

The brothers enter California and, crossing a river, come upon the camp of a lone prospector. As Eli investigates, the prospector sneaks up on Eli from behind and points his gun at him. The prospector asks whether Eli is after a red-haired she-bear, upon which a man named Mayfield has put a bounty of a hundred dollars. Charlie comes out from the woods and shoots the prospector in the head, killing him instantly. The brothers root around and soon find the prospector’s collection of gold, nearly two hundred dollars’ worth.

They are about to leave the prospector’s camp when they see the abandoned boy arriving. The boy is bloodied and dazed, and says he was attacked by four men hunting a red-haired she-bear. The boy asks to go with them, but again the brothers decline his request. Eli gives him some of the gold and tells him to go back to Jacksonville.

Later, Eli and Charlie come across the famed red-haired she-bear. After some discussion, Charlie and Eli decide to kill the bear, take its pelt, and present the prize to Mayfield.

The brothers arrive in the town of Mayfield, which is named after the man who runs it. They meet Mayfield in his hotel and present him with the bearskin. Mayfield pays them, and they decide to stay the night in the hotel. Charlie stays to drink brandy with Mayfield while Eli leaves. The lobby is filled with whores who work at the hotel as well as the trappers, who are mad that the brothers killed the bear and kept them from a payday. One of the women is skinnier and more mysterious than the others, and...

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