African–Americans (AA) have increased prostate cancer risk and a greater mortality rate than European–Americans (EA). AA exhibit a high prevalence of vitamin D deficiency. We examined the global prostate transcriptome in AA and EA, and the effect of vitamin D₃ supplementation. Twenty-seven male subjects (ten AA and 17 EA), slated to undergo prostatectomy were enrolled in the study. Fourteen subjects received vitamin D₃ (4000 IU daily) and 13 subjects received placebo for 2 months prior to surgery. AA show higher expression of genes associated with immune response and inflammation. Systems level analyses support the concept that Inflammatory processes may contribute to disease progression in AA. These transcripts can be modulated by a short course of vitamin D₃ supplementation.