Bleomycin has a chemical toxicity capable of inducing superoxide radicals, which are suggested to play an important part in bleomycin-induced pulmonary fibrosis. We have recently established a mouse model for scleroderma induced by repeated local injections of bleomycin. In this study, we examined the inhibitory effect of superoxide dismutase on the development of dermal sclerosis induced by bleomycin using this mouse model. PC-superoxide dismutase, which is a lecithinized superoxide dismutase with high tissue accumulation and long half-life in blood, was administered (3000 U per kg; dissolved in 5% mannitol) 3 h before the injection of bleomycin in C3H mice for 3 wk. Systemic PC-superoxide dismutase markedly inhibited the development of dermal sclerosis, which was also accompanied by a decrease in the number of infiltrating mast cells and eosinophils. Furthermore, the hydroxyproline content in the skin was significantly reduced, as compared with mice treated with bleomycin only or bleomycin and 5% mannitol. In a separate experiment, after the development of dermal sclerosis following treatment with bleomycin for 3 wk, PC-superoxide dismutase was administered for 2 wk. Histologic examination again revealed a reduction of dermal sclerosis, followed by a significant associate in the number of both mast cells and eosinophils. The hydroxyproline content in the skin was not significantly decreased, however, even after injections of high amounts of PC-superoxide dismutase (30,000 U per kg). These results support the involvement of oxygen free radicals in bleomycin-induced dermal sclerosis, and also indicate that administration of superoxide dismutase may be effective in the therapeutic approach in systemic sclerosis.