Background: The mortality from prostate cancer (PCA) is high in Hispanic Puerto Rican males (HPRM) living on the island of Puerto Rico (PR) and in African American (AA) menliving in the continental US. The PR population is a racially admixed population with significant West African Ancestry(WAA). We hypothesized that WAA was associated with PCA in the HPRM population. Methods: A case/control study was performed recruiting subjects from PR (HPRM) and Texas (AA). Controls (N = 342) were healthy men (209 AA and 133 PR) with no cancer history and PSA < 2.5 ng/ml and a negative Digital Rectal Examination (DRE). Cases (N = 491) were radical prostatectomy specimens (RPS) from 291HPRM and 200AA. DNA was extracted from whole blood of controls and from paraffin embedded normal seminal vesicle from the RPS. We assessed the association of PCA and aggressiveness with genetic ancestryusing an Ancestry Informative Marker panel (AIMs) and with 15 previously associated single nucleotide polymorphisms (SNPs). Ancestry was determined using the STRUCTURE software. The difference in SNPs frequency between various groups was assessed using Pearsons’ Chi square test. The ancestry data were compared between groups using Wilcoxon rank-sum test. Gleason Score (GS) and pathologic stage (pT) were used to define low risk (GS ≤ 7[3+4]),pT ≤ pT2) and high risk (GS ≥ 7[4+3],pT > pT2) PCA. All statistical analyses were done using SAS and STATA. Results: There were significant differences in WAA between AA and the HPR men (p < 0.0001). No difference in ancestry was found between HPRM cases and controls. Among HPRM cases WAA was not associated with disease severity based upon risk group, GS or pT. Among AA controls WAA was significantly higher than in cases. No correlation was found among AA cases with WAA and risk group,pT, or GS. However SNP rs7824364 (chromosome 8q24 region) was significantly associated with PCA in both AA (p < 0.0001) and HPRM (p = 0.0001). Conclusions: We found no association between increasing WAA and prostate cancer presence or aggressiveness among HPRM or AA men. Additional genetic loci studied in tandem with clinical epidemiologic and biologic data to characterize PCA in these two high risk cohorts are in progress.