Recently, the 8q24 region has been identified as a prostate cancer susceptibility locus in a genome-wide scan of prostate cancer families in Iceland and an admixture scan of African Americans. Further investigations of variants at 8q24 have shown the existence of additional single nucleotide polymorphisms (SNPs) that enhance prostate cancer risk, suggesting the possibility of multiple regions harboring variants for the disease. In the present population-based study of Caucasians (1,308 cases and 1,266 controls) and African Americans (149 cases and 85 controls), we tested the association between prostate cancer and 23 SNPs in the 8q24 region. Fourteen SNPs in Caucasians and 5 SNPs in African Americans were significantly associated with risk of prostate cancer after adjusting for multiple comparisons; of these, 5 SNPs in Caucasians and 3 in African Americans were independently associated with risk. The strongest association was for rs6983561 (carriers of any C allele) with an odds ratio of 1.6 (95% confidence interval, 1.1-2.1) in Caucasians; variants in rs979200, rs1016343, rs7837328, and rs10090154 were also independently associated with risk. In African Americans, the strongest association was for rs7000448 (carriers of any T allele) with an odds ratio of 3.4 (95% confidence interval, 1.3-8.7). In addition, two SNPs that extend the boundaries of the 8q24 region were significantly associated with risk: rs979200 at the centromeric boundary and rs3891248, located in the first intron of the c-MYC gene (IVS1-355), which identifies a new telomeric boundary.