The inhibitory effect of polyinosinic-polycytidylic acid (Poly IC), an inducer of interferons, on bleomycin-induced lung collagen accumulation was investigated in mice. Poly IC (10 mg/kg, intraperitoneally) or saline was given for 2 days and immediately prior to intratracheal instillation of bleomycin (0.125 units/mouse) or an equivalent volume of saline and thereafter daily for 13 days. Lung hydroxyproline levels in saline-saline (control), Poly IC-saline (Poly IC), bleomycin-saline and bleomycin-Poly IC groups averaged 279, 287, 459, and 358 micrograms/lung, respectively. The bleomycin + Poly IC mice had significantly less lung hydroxyproline than bleomycin mice, but significantly more hydroxyproline than control or Poly IC mice. Similarly, bleomycin + Poly IC mice had significantly less protein in bronchoalveolar lavage fluid (BALF) supernatant than bleomycin mice, but significantly more protein than control or Poly IC mice. Total cell counts for cells recovered from BALF showed significant increases of 174 and 167% in bleomycin and bleomycin + Poly IC as compared to controls, while the Poly IC group showed a significant decrease of 47% which was primarily due to a decrease in alveolar macrophages. The bleomycin group had significantly more neutrophils, monocytes, macrophages, and lymphocytes than control mice, while bleomycin + Poly IC mice lacked the significant increase in lymphocytes. Bleomycin + Poly IC mice had significantly more monocytes than the bleomycin group. All bleomycin-treated mice had lung lesions, but no lesions were observed in control or Poly IC mice. Bleomycin + Poly IC mice had significantly more (58%) lesions than bleomycin. In contrast, the volume of interstitial lesion in bleomycin + Poly IC mice showed significantly less extracellular fibers (decreased by 62%) and no difference in fibroblasts as compared to bleomycin mice. Fibrotic lesions in bleomycin mice were multifocal and varied from large areas of organized connective tissue to thickened septa lined by cuboidal epithelial cells. Interstitial lesions in bleomycin + Poly IC had a significantly greater volume of mononuclear phagocytes and lymphocytes, but less organized connective tissue than the bleomycin group. Poly IC treatment ameliorated bleomycin-induced lung collagen accumulation.