The variants within the human melanocortin 1 receptor (MC1R) gene are associated with an increased risk of different skin cancers. In this study, we genotyped by direct sequencing, 529 cases of basal cell carcinoma of the skin (BCC) and 533 healthy controls for polymorphisms in the entire MC1R gene. In addition to 10 common polymorphisms, we detected 23 rare variants in the gene. The presence of any nonsynonymous MC1R variant was associated with an increased risk in the carriers (odds ratio OR 1.66, 95% confidence interval CI 1.28-2.14) corresponding to a population attributable fraction of about 27%. The odds ratio for the risk in the carriers of 2 MC1R variants was 2.69 (95% CI 1.77-4.08). The risk of BCC in the carriers of MC1R variants with fair complexion was almost twice as much as in the corresponding noncarriers. The carriers of the R163Q variant with a medium skin complexion were at a 3-fold higher risk than the noncarrier counterparts. The interaction, of effect on the BCC risk, between the MC1R variants and types of skin response to sun exposure was greater than multiplicative. We also observed a multiplicative interaction of risk due to the MC1R variants and the common allele (high risk) of the T241M polymorphism in the XRCC3 gene. Our data confirmed the status of the nonsynonymous MC1R variants as independent genetic risk factors for BCC. However, the mechanism through which the variants influence the risk likely involves complex interactions with other genetic and host risk factors.