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When Ceppi's Overland freight from St. Louis arrives at McKenzie's trading post in Wyoming, McKenzie refuses to give Bess Johnson, a Mormon who arrived two weeks earlier, the medicine Ceppi has brought to fight an epidemic of smallpox at her valley settlement three days away. McKenzie explains that Little Otter, the new chief of the Blackfeet, has threatened to burn the post down if he lets her have the medicine. Unlike the old chief, Bear Paw, Little Otter wants to wipe out all the whites in his territory, and has refused to allow hunting or trapping. To escort her to the valley, Bess enlists the aid of gunfighter Dan Kree, who has just arrived with the freighters on his way to Oregon, hoping to get away from people. With them go Taslatch, an Indian whose tongue has been cut out by the Blackfeet for telling the Mormons about the valley; Gabe, a trapper trying to locate his partner Ez; and Brill, a gambler who is attracted to Bess and believes that the Mormons have a secret gold mine in the valley. At moonrise, they make off with the medicine. After riding all night, they set up camp while Gabe goes to look for signs of Ez. Gabe returns with ominous news that he has found an animal in Ez's trap, dead for three or four days, but no sign of Ez. As they sleep, Dan, despite Bess's entreaties of friendship, refuses to sleep near the group, saying he doesn't like people around when his eyes are closed. The next day, Brill tries to talk Dan into joining him in his scheme to get the Mormons' mine, but Dan rebuffs him, saying he wouldn't trust him. After they move on, Little Otter and his people find the warm stones of the group's campfire. When the group is one day away from the valley, the Blackfeet pass nearby, and the party hides behind rocks. Dan is attacked by a poisonous snake, and Bess cuts the wound from his arm and sucks out the poison. When she sees a scar on the side of his chest, he explains that he got it from his own brother, who shot him in the back during an argument. After he killed his brother, his own wife took a shot at him. He says he hasn't trusted anyone since. At night, Bess relates that after the Mormons settled in the valley, the Blackfeet tried to burn them out, but the wind changed and caught the Blackfeet on the valley floor. They escaped, but Bear Paw, sure that the spirits were angry, made a treaty with the Mormons and declared that the Blackfeet would not enter the valley again. When Dan walks away after Bess entreats him to stay near, Brill tries to talk her into taking the gold from the valley and going with him to New Orleans. When he grabs her, Taslatch intercedes, and after Bess has Taslatch release him, Brill is about to fire at the Indian when Dan stops him. She tries to thank Dan, but he says he acted in his own interest, as a shot would bring the Blackfeet. They soon come upon Ez, wandering about in hysterics, his eyes burned out by Little Otter and his people, who took his pelts and said no white eyes shall look on Blackfeet land again. When Brill suggests they give Gabe and Ez enough food to return to McKenzie's, Dan objects that alone they would never make it past Little Otter. Although Gabe volunteers to go back, knowing of Bess's concern to return soon with the medicine, she painfully decides to wait until nightfall and try to make it to the valley together. As she sobs, Dan comforts her. Bess tells him her belief that every human being is responsible for every other human being, and says that the twenty families waiting for the medicine would rather lose it than turn their backs on a man in need, even if it meant their lives. After Taslatch is shot and killed with an arrow, a battle ensues. Dan rescues Bess, and following a hand-to-hand fight, the Indians retreat. They begin to chant in the distance, asking help from the spirits. As they wait, Dan reveals to Bess that his wife had their marriage set aside and has taken up with a riverboat owner. Little Otter comes to talk and offers them safe passage if they will give up the medicine. Although Brill wants to make the deal, Dan proposes they stall until after nightfall. Little Otter is told that they have to ask their own spirits' advice after the full moon. Because the Blackfeet never make a move without consulting spirits, Little Otter agrees. At night, the group slips away, but the next day as they near the last mountain before the valley, Little Otter and his people block their path and demand the medicine. The whites take cover in the rocks, and during the subsequent battle, Ez goes into hysterics, and when Gabe goes to help, Little Otter shoots them both. Dan then shoots Little Otter. When the other Indians come to take their chief's body away, Dan prevents Brill from shooting them. Brill now asks Bess to point out the mine. She reveals that it is near Tombstone and that she and her people worked it and asked to be paid in nuggets. Exasperated, Brill plans to sell the medicine to McKenzie or the Blackfeet and starts off with it. Bess shoots a rifle, but Dan deflects the shot. Dan then traps Brill from behind and shoots him as he draws. As Bess and Dan ride toward the valley, she asks him if he'll stay, and he says maybe he will.