Exposure to mid-range ultraviolet radiation (UVR) [280 – 320 nm, ultraviolet B (UVB) radiation] inhibits the acquisition of delayed-type hypersensitivity in mice and contact hypersensitivity in rodents and humans. Intraperiotoneal administration of interleukin 10 (IL-10) inhibits the sensitization of mice to alloantigens for a delayed-type hypersensitivity reaction and administration of neutralizing antibodies to IL-10 largely, but not totally, blocks the UVR-mediated suppression of the ability to sensitize mice. This suggests that these inhibitory effects of UVB radiation may be mediated by release of IL-10. To test this hypothesis directly, IL-10 gene-targeted (IL-10T) mice lacking expression of IL-10 were examined for the ability of UVB radiation to suppress induction of delayed-type hypersensitivity to alloantigens. IL-10T mice were completely resistant to UVB-induced immunosuppression in this system. Interestingly, UVB radiation could suppress in IL-10T mice the induction of contact hypersensitivity to a hapten applied to the skin at a site distant of irradiation, supporting the concept that regulation pathways of delayed-type hypersensitivity and contact hypersensitivity responses by UVR differ. These data provide additional understanding of the mechanisms of immunosupression induced by UVR and suggest that IL-10 release subsequent to UVB radiation may play a role in the growth of immunogenic UVB-induced cutaneous malignancies in the primary host.