Germline mutations of CDKN2A and CDK4 have been identified in 20-40% of families with ≥3 melanoma patients. In this study, we analyzed whether the anatomic distribution of melanoma differed between CDKN2A or CDK4 mutation carriers and those without a mutation. Data for this study came from a non-population-based family study of individuals with a family history of melanoma who were enrolled in NCI clinical protocol 02-C-0211, which examines genetic and phenotypic risk factors for melanoma. Patients in this analysis had at least one first or second degree relative with melanoma plus a personal history of melanoma. Pathology reports were used to confirm the anatomic location of each melanoma. Overall, 269 melanoma patients (No Mutation Identified (NMI) = 108 patients, 170 melanomas; CDKN2A Mutation (CDKN2A+) = 146 patients, 356 melanomas; CDK4 Mutation (CDK4+) = 15 patients, 54 melanomas) had pathology reports that included anatomic location. The number of non-truncal melanomas was significantly higher (by trend test) in CDKN2A or CDK4 mutation carriers versus NMI controls (CDKN2A+ vs. NMI: odds ratio = 1.59; 95% CI, 1.12-2.24; p=0.009) (CDK4+ vs. NMI: odds ratio = 3.10; 95% CI, 1.65-5.82; p<0.001). Most mutation carriers (72% CDKN2A+; 93% CDK4+) had ≥1 non-truncal melanoma versus only 46% of NMI patients. Tumor location was independent of body surface area. The anatomic distribution of melanoma within each group (NMI, CDKN2A+, CDK4+) was similar for small and large melanoma families albeit with all patients treated independently. Mutation carriers, CDKN2A and CDK4, were significantly more likely to have non-truncal melanoma tumors than NMI patients. Non-truncal sites are less likely to be covered by clothing, suggesting that ultraviolet light may contribute differently to melanoma development in mutation carriers. Future studies are needed to investigate these findings. Our analysis was restricted to melanoma-prone families and thus may not be representative of all melanoma patients.