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Background: Promotion of the HIV epidemic by aflatoxin is postulated but not yet established. Sub-Saharan populations commonly consume food contaminated by mycotoxins, particularly aflatoxins (predominantly found in peanut, maize, rice, and cassava) and fumonisins, which occur primarily in maize. Aflatoxin promotes hepatocellular cancer, and fumonisin may promote esophageal cancer. Objectives: This analysis was undertaken to test the hypotheses that consumption of mycotoxin-prone staple foods is 1) related to the incidence of HIV infection in Africa and 2) related to 'signature' cancer rates confirming exposure to aflatoxins and fumonisins. Design: World Health Organization data for causes of death and the Food and Agriculture Organization per capita consumption data for commodities in sub-Saharan Africa were used. Per capita Gross Domestic Product and the percentage of Muslims (%Muslim) were the socioeconomic data sets exploited. Relations between causes of mortality, consumption of mycotoxin-prone foods, and socioeconomic variables were evaluated. Models for HIV transmission as a function of maize consumption and %Muslim were estimated. Results: HIV and esophageal cancer deaths were significantly related to maize but were inversely related to %Muslim and rice consumption. HIV infections were minimized (74 compared with 435/100,000 people; odds ratio: 2.41; 95% CI: 1.73, 3.24; P [less than or equal to] 0.0001) by the combination of low maize consumption and above-median %Muslim. Hepatocellular cancer deaths were positively related to rice but negatively related to maize consumption. Conclusions: HIV transmission frequency is positively associated with maize consumption in Africa. The relation between cancer and food suggests that fumonisin contamination rather than aflatoxin is the most likely factor in maize promoting HIV. Changes to the quality of maize may avoid up to 1,000,000 transmissions of HIV annually. Am J Clin Nutr 2010;92:154-60. doi: 10.3945/ajcn.2009.28761.