Many possible treatments for pulmonary fibrosis have been investigated, but except for some current clinical trials, none have succeeded in clinical trials. On the basis of the antioxidant action of bilirubin (BIL), we examined the effects of hyperbilirubinemia on the development of bleomycin (BLM)-induced pulmonary fibrosis in rats. The animals' plasma BIL level was kept within 3 and 10 mg/dl by repeated intravenous infusion of a high dose of BIL. We studied the inhibitory effects of hyperbilirubinemia on BLM-induced pulmonary fibrosis through histopathologic and biochemical analyses. Mortality of rats with BLM-induced pulmonary fibrosis was significantly lower in the three groups with hyperbilirubinemia. The ameliorating effect of hyperbilirubinemia on pulmonary fibrosis was shown by lung histology, as well as by a decreased lung content of hydroxyproline and reduced bronchoalveolar lavage fluid (BALF) concentration of transforming growth factor (TGF)-beta(1). The number of polymorphonuclear leukocytes and lymphocytes in BALF was also decreased in the groups with hyperbilirubinemia. Furthermore, oxidative metabolites of BIL in urine were present at significantly higher levels in BLM-treated rats with hyperbilirubinemia than in those without hyperbilirubinemia. These data suggest that the antioxidative action of BIL can attenuate BLM-induced pulmonary fibrosis, partly by inhibiting lung inflammation and production of TGF-beta1.