The primary risk-modifying factors for prostate cancer are still a matter of debate. This work proposes and examines the hypothesis that the apolipoprotein E epsilon4 (ApoE4) allele and diet are important risk factors for prostate cancer. The hypothesis was evaluated in an ecological study involving 122 countries for which prostate cancer rates for 2002, ApoE4 allele prevalence, dietary supply values, and per capita gross domestic product (GDP) data were available, and for which there were at least 250,000 inhabitants. In addition, a subset of 102 countries with ApoE4 prevalence of less than 30% was also used. In the full data set, per capita GDP, lack of cereal consumption, milk protein and ApoE4 were significantly correlated with incidence, explaining 60% of the variance. In the 102-country subset of 102, per capita GDP, ApoE4 prevalence, and milk protein explained 62% of the variance of prostate cancer incidence, while lack of cereal consumption, ApoE4 prevalence and per capita GDP explained 55% of the variance of prostate cancer mortality rates. Cholesterol has been identified as an important risk factor for prostate cancer. The ApoE4 allele increases cholesterol production and cereal consumption lowers serum cholesterol levels. The ApoE4 allele is an important risk factor for Alzheimer's disease, and cholesterol is a risk factor and cereals a risk reduction factor. The ApoE4-diet-GDP hypothesis may explain the higher risk of prostate cancer for African Americans and should form the basis for further studies.