The incidence of prostate cancer in the United States is second only to skin cancers, and the disease kills almost the same number of men as breast cancer does women. Relatively few risk factors are known for prostate cancer, although several lines of evidence suggest that vitamin D may be an important determinant of prostate cancer risk. A series of common polymorphisms in the vitamin D receptor gene were recently reported to be associated with bone density and risk of osteoporosis (Morrison et al., Nature (Lond.), 367: 284-287, 1994). These genetic variants have been correlated with both circulating levels of active vitamin D hormone and in vitro measures of gene expression (Morrison et al., Nature (Lond.), 367: 284-287, 1994). We tested the hypothesis that vitamin D receptor gene polymorphisms are associated with prostate cancer risk using a case-control study of 108 men undergoing radical prostatectomy and 170 male urology clinic controls with no history of cancer. Among the white control group, 22% were homozygous for the presence of a TaqI RFLP at codon 352 (genotype tt), but only 8% of cases had this genotype (P < 0.01). A similar trend was seen among the small number of blacks in this study (13% for controls, 8% for cases), although the difference was not statistically significant. Race-adjusted combined analysis suggests that men who are homozygous for the t allele (shown to correlate with higher serum levels of the active form of vitamin D) have one-third the risk of developing prostate cancer requiring prostatectomy compared to men who are heterozygotes or homozygous for the T allele (odds ratioMH = 0.34; 95% confidence interval, 0.16-0.76; P < 0.01). These results support recent ecological, population, and in vitro studies suggesting that vitamin D is an important determinant of prostate cancer risk and, if confirmed, suggest strategies for chemoprevention of this common cancer.