The existing bleomycin (BLM)-rodent model of lung fibrosis requires large doses and is often associated with morbidity and high mortality. We have developed an intratracheal multiple-dose BLM-hamster model of lung fibrosis. In this model, 3 consecutive doses of BLM (2.5 U, 2.0 U and 1.5 U/5mL/kg) were instilled intratracheally, one dose per week. The hamsters were killed at 10, 20, 30, 60 and 90 days after the last IT instillation and the lungs were lavaged or perfused with saline. This regimen of BLM administration was devoid of morbidity and caused only 6% overall mortality. Lung prolyl hydroxylase activity at 10 days and hydroxyproline content at 20, 30, 60 and 90 days were significantly higher than noted for the controls. Bronchoalveolar lavage fluid-supernatant protein and the total number of recovered cells of all types were significantly higher than observed for the controls at all times, except at 90 days. Lungs showed a multifocal mixed mononuclear infiltrate at 10 and 20 days and septal fibrosis, which was most severe and organized at 30 days and less severe at 60 and 90 days. The parenchymal lesions were significantly greater than those of the controls at all times, except at 10 days. This model, which required only 6 U BLM/kg, induced a moderate level of lung fibrosis. It has been concluded, therefore, that this model, inasmuch as it is not associated with an overwhelmingly acute inflammation, would be more applicable for screening potential antifibrotic agents than existing models of lung fibrosis.