The hemochromatosis C282Y mutation is present in up to 12.5% of people in populations of northern and central European origin. The prevalence of this mutation suggests that it may confer some type of epidemiologic advantage. One hypothesis has proposed that female heterozygotes have enhanced dietary iron absorption during their reproductive years, but evidence in support of this concept is not available. A second hypothesis is based on the observation that macrophages in iron-loaded C282Y homozygotes are very low in iron. These persons would be predicted to have increased resistance to pathogens that require iron for growth in macrophages. Notable examples of such pathogens are S. typhi and M. tuberculosis, the bacteria that cause typhoid fever and tuberculosis. Several cellular models that provide evidence for the low-iron macrophage hypothesis have recently been described.