Genotyping of a 615 kb region within 8q24 with 49 haplotype-tagged single-nucleotide polymorphisms (SNPs) in 2109 samples (797 cases and 1312 controls) of two ethnic/racial groups found SNPs that are significantly associated with the risk for prostate cancer (PCa). The highest significance in Caucasian men was found for rs6983267; the AA genotype reduced the risk for PCa [odds ratio (OR) = 0.48, 95% confidence interval (CI) = 0.35-0.65, P = 2.74 x 10(-6)]. This SNP also had a significant independent effect from other SNPs in the region in this group. In Hispanic men, rs7837328 and rs921146 showed independent effects (OR = 2.55, 95% CI = 1.51-4.31, P = 4.33 x 10(-4), OR = 2.09, 95% CI = 1.40-3.12, P = 3.13 x 10(-4), respectively). Significant synergist effects for increasing numbers of high-risk alleles were found in both ethnicities. Haplotype analysis revealed major haplotypes, containing the non-risk alleles, conferred protection against PCa. We found high linkage disequilibrium between significant SNPs within the region and SNPs within the CUB and Sushi Multiple Domains 1 gene (CSMD1), on the short arm of chromosome 8 in both ethnicities. These data suggest that multiple interacting SNPs within 8q24, as well as different regions on chromosome 8 far beyond this 8q24 candidate region, may confer increased risk of PCa. This is the first report to investigate the involvement of 8q24 variants in the susceptibility for PCa in Hispanic men.