Abstract: Bloodletting—the practice of letting blood out to cure a patient—was for centuries one of the main therapies in the West. We lay out three potential explanations for bloodletting’s cultural success: that it was efficient, that it was defended by prestigious sources—in particular ancient physicians—, and that cognitive mechanisms made it a particularly attractive practice. To test these explanations, we first review the anthropological data available in eHRAF. These data reveal that bloodletting is practiced by many unrelated cultures worldwide, where it is performed for different indications and in different ways. This suggests that the success of bloodletting cannot only be explained by its medical efficiency or by the prestige of Western physicians. Instead, some universal cognitive mechanisms likely make bloodletting an attractive form of therapy. We further test this hypothesis using the technique of transmission chains. Three experiments are conducted in the U.S., a culture that does not practice bloodletting. Studies 1 and 2 reveal that stories involving bloodletting survive longer than some other common therapies, and that the most successful variants in the experiments are also the most successful variants worldwide. Study 3 shows how a story about a mundane event—an accidental cut—can turn into a story about bloodletting. This research demonstrates the potential of combining different methodologies—review of anthropological data, experiments, and modeling—to investigate cultural phenomena.