Although skin tumors are highly immunogenic, exposure to UV radiation is known to suppress immune responses via regulatory T cells. Specifically, the activity of cytotoxic lymphocyte-associated antigen-4 (CTLA-4) is integral in regulating the development of UV-induced tolerance and, concomitantly, skin cancers. Due to the inverse relationship between tumor surveillance and autoimmunity, we hypothesize that the same genetic variant in the CTLA4 locus that increases risk for autoimmune diseases is associated with decreased risk of non-melanoma skin cancer (NMSC). We analyzed whether the polymorphism CT60 or haplotypes of CTLA4 influence odds of developing the major types of NMSC, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), in a population-based case-control study of Caucasians in New Hampshire (849 controls, 930 BCC, and 713 SCC). The CTLA4 CT60 GG genotype was associated with decreased odds for BCC and SCC, controlling for age, sex, lifetime number of severe sunburns, and skin type [BCC: odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.5-0.9; SCC: OR, 0.7; 95% CI, 0.5-1.0]. For BCC, this decrease was apparent largely among those with a higher lifetime number of severe sunburns (P interaction = 0.0074). There were significantly decreased odds of disease associated with two haplotypes, which possess the CT60 G allele. Additionally, lifetime number of severe sunburns modestly altered the effects of the CTLA4 haplotypes in BCC, and the association seemed driven by the CT60 single nucleotide polymorphism. In conclusion, genetic variation at the CTLA4 locus may be etiologically important in NMSC, the most prevalent malignancy in the United States.