The XPD gene is involved in the nucleotide excision repair pathway removing DNA photoproducts induced by UV radiation. Genetic variation in XPD may exert a subtle effect on DNA repair capacity. We assessed the associations between two common nonsynonymous polymorphisms (Asp312Asn and Lys751Gln) with skin cancer risk in a nested case-control study within the Nurses' Health Study (219 melanoma, 286 squamous cell carcinoma, 300 basal cell carcinoma, and 874 controls) along with exploratory analysis on the haplotype structure of the XPD gene. There were inverse associations between the Lys751Gln and Asp312Asn polymorphisms and the risks of melanoma and squamous cell carcinoma. No association was observed between these two polymorphisms and basal cell carcinoma risk. We also observed that the association of the 751Gln allele with melanoma risk was modified by lifetime severe sunburns, cumulative sun exposure with a bathing suit, and constitutional susceptibility score (P for interaction = 0.03, 0.04, and 0.02 respectively). Similar interactions were also observed for the Asp312Asn. Our data suggest these two XPD nonsynonymous polymorphisms may be associated with skin cancer risk, especially for melanoma.