As an evolutionary response to prevent malaria infection, most Africans do not express the Duffy Antigen/Receptor for Chemokines (DARC) on their red blood cells. Results from experimental studies suggest that DARC expression inhibits prostate-tumor growth. We tested the hypothesis that men of African descent who lack DARC expression are at increased risk of prostate cancer. A case-control study involving 81 age-matched pairs was conducted in Jamaica. Participants were interviewed to collect data, and they donated blood for determination of DARC expression. Logistic regression was used to estimate associations with prostate cancer and aggressive disease. Little or no association was observed between erythrocyte DARC expression and prostate cancer or between DARC expression and aggressive disease. These associations changed little when adjusting for other potential confounders. Our results do not support an effect of erythrocyte DARC expression on the risk or progression of prostate cancer in men of African descent.