The Duffy antigen/receptor for chemokines (DARC) is a promiscuous chemokine receptor that binds to members of the CXC chemokine family possessing angiogenic properties. The DARC is expressed on erythrocytes and endothelial cells and is required for Plasmodium vivax infection of erythrocytes. Approximately 70% of African‐Americans lack erythrocyte expression of the DARC as a genetic mechanism of protection against malaria infection. African‐American men have a 60% greater incidence of prostate cancer and a 2‐fold higher mortality rate than Caucasian men. Using a transgenic model of prostate cancer with DARC‐deficient mice, we tested the hypothesis that lack of DARC expression on erythrocytes contributes to enhanced prostate tumor growth. In vitro, erythrocytes from wild‐type mice but not DARC‐deficient mice cleared angiogenic chemokines produced by prostate cancer cells and reduced endothelial cell chemotaxis. In vivo, tumors from DARC‐deficient mice had higher intra‐tumor concentrations of angiogenic chemokines, increased tumor vessel density, and greatly augmented prostate tumor growth. The data suggest that the DARC functions to clear angiogenic CXC chemokines from the prostate tumor microcirculation and that the lack of erythroid DARC, as occurs in the majority of African‐Americans, may be a contributing factor to the increased mortality to prostate cancer in this popula‐tion.—Shen, H., Schuster, R., Stringer, K. F., Waltz, S. E., Lentsch, A. B. The Duffy antigen/receptor for chemokines (DARC) regulates prostate tumor growth. FASEB J. 20, 59–64 (2006)