The incidence and mortality rates of prostate cancer are significantly higher in African-American men when compared to European-American men. We tested the hypothesis that differences in tumor biology contribute to this survival health disparity. Using microarray technology, we obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. These tumors were matched on clinical parameters. We also evaluated 18 non-tumor prostate tissues from 7 African-American and 11 European-American patients. The resulting datasets were analyzed for expression differences on the gene and pathway level comparing African-American with European-American patients. Our analysis revealed 162 transcripts to be differentially expressed between African-American and European-American prostate cancer patients at a false discovery rate of 5% or less. Using a disease association analysis, we identified a common relationship of these transcripts with autoimmunity and inflammation. These findings were corroborated on the pathway level with numerous differentially expressed genes clustering in immune response, defense response, antigen presentation, B-cell/T-cell function, cytokine signaling, and inflammatory response pathways. Most commonly, the genes involved in these pathways were more highly expressed in tumors of African-American patients when compared with those of European-American patients. Amongst the immune-specific genes over-expressed by African-American patients was indoleamine 2,3-dioxygenease, HLA-E, and HLA-G. All three of these genes are well-known contributors of immunologic tolerance in tumors. Furthermore, a distinctive interferon signature was identified in the African-American prostate tumors, suggesting the possibility of viral involvement in disease etiology in this African-American population. In conclusion, the gene expression profiles of prostate tumors indicate prominent differences in tumor immunobiology between African-American and European-American men. The profiles portray the existence of a distinct tumor microenvironment in these two patient groups.