We determined mutations in the BRAF, N-ras, and CDKN2A genes in 27 histologically diverse melanocytic nevi and corresponding surrounding tissues from 17 individuals. Mutations in the BRAF and N-ras gene were found in 22 nevi (81%) from 16 individuals (94%). The predominant BRAF mutation T1799A (V600E) was detected in 18 nevi; 1 nevus had a novel A1781G (D594V) mutation in the same gene and 3 nevi had mutations in codon 61 of the N-ras gene. In 4 individuals both nevi carried a BRAF mutation, whereas in 2 other individuals 1 nevus showed a BRAF mutation and the second nevus had an N-ras mutation. In 2 individuals normal skin distant from nevi showed a BRAF mutation. No mutations were detected in the CDKN2A gene. The mutations in the BRAF and N-ras genes, in this study, were not associated with histologic type, location, skin type, size, or numbers of nevi. Our results suggest that mutations in the BRAF gene and to some extent in the N-ras gene represent early somatic events that occur in melanocytic nevi. We hypothesize the dual effect of solar ultraviolet irradiation on melanoma, through mutagenesis and by increasing the number of melanocytic nevi, many of which carry a BRAF or N-ras mutation.