The vitamin D receptor (VDR) gene has been associated with prostate cancer, although previous results are somewhat equivocal. To further study this, we did a family-based case-control study (N = 918) of the association between prostate cancer and six common VDR variants: Cdx2, FokI, BsmI, ApaI, TaqI, and the poly-A microsatellite. Looking at each variant alone, only FokI and ApaI were associated with disease. The FokI FF genotype was inversely associated with prostate cancer among men with less advanced disease (i.e., Gleason score <7 and tumor stage <T2c), where the odds ratio OR was 0.56 [95% confidence interval (95% CI), 0.31-1.01; P = 0.05]. ApaI, carrying one or two copies of the A allele, exhibited a weak inverse association with disease (OR, 0.64; 95% CI, 0.39-1.03; P = 0.06); this association was strengthened in Caucasian men with more advanced disease (OR, 0.44; 95% CI, 0.21-0.93; P = 0.03). We observed inverse associations between disease and the four-locus FBAt haplotype (OR, 0.48; 95% CI, 0.30-0.76; P = 0.002) and the fbaT haplotype (OR, 0.60; 95% CI, 0.38-0.95; P = 0.03; i.e., in comparison with the FbaT haplotype). These were stronger among men with more advanced disease: for FBAt, the OR was 0.31 (95% CI, 0.16-0.61; P = 0.0008); for fbaT, the OR was 0.32 (95% CI, 0.16-0.64; P = 0.001). These observations support a role for VDR variants in prostate cancer risk but suggest that any potential causal variant(s) may reside on the haplotypes reported here. This would help explain the somewhat equivocal results for VDR genotype-level associations with prostate cancer.