The melanocortin-1 receptor (MC1R) and P gene product are two important components of the human pigmentary system that have been shown to be associated with red hair/fair skin and cause type II oculocutaneous albinism, respectively. However, their contribution to inter-individual variation at the population level is not well defined. To this end, we genotyped 3 single nucleotide polymorphisms (SNPs) in the MC1R gene (Arg67Gln, Gln163Arg, Val92Met) and 2 SNPs in the P gene (IVS 13-15 and Gly780Gly) in 184 randomly ascertained Tibetan subjects, whose skin color was measured as a quantitative trait by reflective spectroscopy. Single locus analyses failed to demonstrate an association between any of the 5 SNPs and skin pigmentation. However, when an epistatic model was applied to the data, a significant gene-gene interaction was identified between Val92Met in MCIR and IVS13-15 in the P gene (F=2.43; P=0.0105). We also discuss the possible mechanisms of how gene interactions arise in signal transduction pathways.