Ultraviolet B radiation (290-320 nm) initiates a dose and wavelength dependent down-regulation of cell-mediated immunity which is critical in experimental ultraviolet radiation (UV) carcinogenesis, preventing immune attack on highly antigenic UV-induced tumors. UV-induced immunosuppression has been demonstrated in humans and may be a risk factor for skin cancer. In this study, we have investigated genetic linkage of the autosomal loci controlling this trait. Previously, we had derived a model describing control of susceptibility to UV-induced immunosuppression in inbred mice by unlinked interacting autosomal and X-linked loci. A genome-wide scan using MIT microsatellite markers was carried out on 100 backcross {BALB/c × (BALB/c × C57BL/6) F 1 } mice derived from the inbred strains BALB/c (low susceptibility) and C57BL/6 (high susceptibility) and tested for systemic UV-induced immunosuppression of a contact hypersensitivity response. The values for % suppression for each animal and the genotype data were used to investigate genetic linkage by multiple regression analysis. Significance was assessed using the permutation test. Both main effects and interactive effects were investigated, first with each genotype marker singly, and secondly, in a novel approach using markers pairwise. A joint model was derived in which all loci and pairs of loci identified were included simultaneously in a multiple regression model. This model indicates four quantitative trait loci (QTLs) with significant main effects, one on chromosome 10 which decreased susceptibility to UV-induced immunosuppression and QTLs on chromosomes 6, 17 and 1 which increased susceptibility. Additionally, loci on chromosomes 14 and 19 showed significant interaction with the locus on chromosome 1. Further investigation indicated a potential three-way interaction involving the loci on chromosomes 1,14 and 19. Genes and Immunity (2000) 1, 251-259.