Previous reports have suggested that the immune system is involved in the lung fibrogenic response to certain agents or treatments. In the present study, we have evaluated the impact of the athymic (nude) mutation on the development of pulmonary fibrosis in mice induced by a single intratracheal instillation of bleomycin (0.75 units/animal). Histologic examination revealed that cellular infiltration, fibroblast proliferation, and connective tissue accumulation were diminished in the nude mice when compared with euthymic (het) control mice. In contrast to control animals treated with saline, total lung hydroxyproline in the nude mouse was not significantly increased at 14 and 30 days after bleomycin treatment. Net collagen synthesis, as assessed by measuring the rate of incorporation of tritiated proline in an organ culture system, was increased above control values in both nude and euthymic mice at 14 days after bleomycin treatment, although these values returned to normal at 30 days. However, lung collagen synthetic rates, normalized to dry lung weights, were significantly higher at 14 days in euthymic bleomycin-treated control mice than in the nude bleomycin-treated animals. The data indicate that the nude athymic mutation protects, at least partially, against bleomycin-induced pulmonary fibrosis, thus suggesting a role for the cellular immune system in regulating the fibrogenic response to this drug.