Single suberythemal exposures of UVA radiation have been shown to block the immunosuppressive effects of UVB radiation in the mouse. The immunoprotection is dependent both on the presence of the cytokine, IFN-γ, and on the induction of the antioxidant stress enzyme, heme oxygenase (HO), in the skin. Recently, the transcriptional response of the HO-1 gene to UVA radiation in cultured human skin fibroblasts was reported to be refractory to a second UVA irradiation. In this study on the hairless mouse, we demonstrate that the inducibility of HO enzyme activity in the skin similarly became refractory to a second UVA irradiation at 24 h but, like the fibroblast response, was restored when the interval between the UVA exposures was increased to 96 h. Under the conditions of refractory HO enzyme induction, the protective effect of UVA radiation against the suppression of contact hypersensitivity induced by UVB radiation or cis-urocanic acid was strongly attenuated but was restored when the interval between UVA exposures was increased to 96 h. The results thus confirm the strong relationship between HO induction and photoimmunoprotection by UVA radiation, and describe a new phenomenon of immunological refractoriness that develops with rapidly repeated UVA exposures.