BACKGROUND. Prostate cancer is a significant public health problem in this country. Substantial data support a plausible role for androgens in the etiology of this disease. The human HSD17B3 gene encodes the testicular (or type III) 17beta-hydroxysteroid dehydrogenase enzyme, which catalyzes testosterone biosynthesis in men. METHODS. We have investigated the G289S (glycine at codon 289 replaced by serine) polymorphism at the HSD17B3 locus as a candidate single nucleotide polymorphism (SNP) for prostate cancer risk in constitutional DNA from 103 Italian prostate cancer patients and 109 Italian disease-free centenarians to assess the role of this SNP in susceptibility to prostate cancer. RESULTS. The G289S polymorphism confers a significant increase in risk for prostate cancer (odds ratio = 2.5; 95% confidence interval, 1.03-6.07) in our study population. CONCLUSION. Our data are consistent with a plausible role of the G289S SNP in prostate cancer susceptibility. Therefore, the HSD17B3 gene may be a plausible candidate gene for prostate cancer risk