Exposure to ultraviolet radiation may reduce prostate cancer risk, suggesting that polymorphism in genes that mediate host pigmentation will be associated with susceptibility to this cancer. We studied 210 prostate cancer cases and 155 controls to determine whether vitamin D receptor (VDR, Taql and Fokl variants), tyrosinase (TYR, codon 192 variant) and melanocortin-1 receptor (MC1R, Arg151Cys, Arg160Trp, Val92Met, Asp294His and Asp84Glu variants) genotypes are associated with risk. UV exposure was determined using a questionnaire. MC1R Arg(160)/Arg(160) homozygotes were at increased risk (P = 0.027, odds ratio = 1.94) while TYR A2/A2 homozygotes were at reduced risk of prostate cancer (P = 0.033, odds ratio = 0.48). These associations remained significant after correction for UV-exposure. Stratification of cases and controls by quartiles of exposure, showed that the protective effect of TYR A1A2 (P = 0.006, odds ratio 0.075) and A2A2 (P = 0.003, odds ratio 0.055) was particularly strong in subjects who had received the greatest exposure. Our data show for the first time, that allelism in genes linked with skin pigment synthesis is associated with prostate cancer risk possibly because it mediates the protective effects of UV. Importantly, susceptibility is associated with an interaction between host predisposition and exposure.