Abstract— Irradiation of the skin with ultraviolet-B (UVB) radiation causes a local and systemic suppression of T-cell-medi-ated immune responses. Recently, N-acetylcysteine (NAC) was found to protect against UVB-induced immunosuppression and several other types of UV damage. The protective effects appeared to be based on the ability of NAC to increase glutathione (GSH) levels by promoting GSH synthesis. In this study, it was investigated whether topical application of NAC was still effective against UVB-induced suppression of contact hypersensitivity if GSH synthesis was blocked. Mice were pretreated with buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, which succeeded in blocking the increase in epidermal GSH after topical application of NAC. Whereas the non-BSO-treated animals showed an increase to around 155% of the control GSH level for all NAC doses tested, only a slight (nonsignificant) increase in epidermal GSH was observed in the BSO-treated animals. Surprisingly, the protective efficacy of NAC against UVB-induced immunosuppression was not affected by the BSO pretreatment. No significant difference between the protective efficacy of NAC in the two groups was observed. Apparently, the antioxidant effect of NAC itself was sufficient to provide protection against UVB-immunosuppression, independent of GSH synthesis.