The effects of a single intratracheal instillation of bleomycin followed by exposure to 70% oxygen for 72 h were studied in hamsters. Mortality increased markedly among hamsters exposed to 70% oxygen for 72 h after bleomycin instillation, compared with animals receiving bleomycin and breathing room air. The lethal dose required to kill 50% of the hamsters at 30 days (LD50, 30 day) for bleomycin alone was 0.73 U/100 g body weight, whereas the LD50, 30 day for bleomycin followed by 70% oxygen fell to 0.23 U/100 g body weight. Using morphometry and light microscopy, we found that the amount of diseased lung increased in hamsters given bleomycin with hyperoxia compared with that in those treated with bleomycin alone. After 0.20 U bleomycin and air, 2.8 +/- 1.6% of the lung was abnormal, but with 0.20 U bleomycin followed by 70% oxygen, 42.7 +/- 17.9% of the lung was abnormal. At bleomycin doses that produced no apparent lesions, the addition of 70% oxygen for 72 h produced focal interstitial fibrosis at 30 days. Neither mortality nor significant histologic changes were seen in hamsters treated with saline followed by exposure to 70% oxygen for 72 h. This study demonstrates that hyperoxia potentiates bleomycin damage and suggests that the use of elevated oxygen concentrations in patients being treated with bleomycin should be minimized.