Objective: To understand the role in prostate cancer risk and aggressiveness, we investigated the expression in prostate tumor and single nucleotide polymorphisms of SLC5A8. Previous studies have suggested that SLC5A8 might function as a tumor suppressor gene, whose silencing by epigenetic changes might contribute to carcinogenesis. Methods: We constructed tissue microarrays from 183 prostate tumor tissues, 43 adjacent non-neoplastic tissues from the same patients, and 13 tissue samples from patients with benign prostatic hyperplasia or prostatic intraepithelial neoplasia. A semiquantitative assessment of SLC5A8 protein expression was determined as the product of immunostaining intensity and the percentage of cells stained. In addition, we compared the frequencies of 4 single nucleotide polymorphisms (rs164365, rs1709189, rs1399236, and rs1681096) in SLC5A8 between 668 prostate cancer cases and 385 controls. Results: SLC5A8 expression was significantly greater in the tumor tissues than in the paired non-neoplastic tissues (P <.0001). In the Moffitt samples, we observed a borderline moderate risk increase in patients with a genotype containing ≥1 "A" allele of rs164365 (odds ratio 1.35, 95% confidence interval 1.00-1.80), especially among tall men (≥70 in.; odds ratio 1.80, 95% confidence interval 1.20-2.68). However, these results were not confirmed in the Cancer Genetic Markers of Susceptibility population. Conclusion: These data suggest that the expression pattern of SLC5A8 might be used as a diagnostic biomarker, and a larger study is required to assess the importance of SLC5A8 single nucleotide polymorphisms in prostate cancer.