Several reports have suggested that patients treated with bleomycin may be at greater risk of developing respiratory failure when exposed to elevated concentrations of oxygen. We studied the interactions of bleomycin and hyperoxia in Syrian golden hamsters. Animals were instilled intratracheally with bleomycin at a dose of 0.5 unit/100 g of body weight, followed immediately by exposure to 70% oxygen for 72 hours. Mortality was 90% in these hamsters, compared to 15% in an age-matched control group treated with bleomycin alone. Postmortem studies revealed that pathologic changes were confined to the lungs which showed severe, hemorrhagic, diffuse alveolar damage. To determine the effect of delaying exposure to hyperoxia, bleomycin at a dose of 0.5 unit/100 g of body weight was instilled and animals were kept in room air for 1 and 2 months before exposure to 70% or 100% oxygen for 72 hours. No significant increase in mortality or interstitial pneumonitis and fibrosis was seen in these groups during or after the hyperoxic exposures. Mortality in controls treated with saline and hyperoxia was zero. We conclude that simultaneous treatment with bleomycin and hyperoxia results in a synergistic effect on mortality and on the development of pulmonary fibrosis. However, there is no synergism if the hyperoxic exposure is delayed for at least 1 month following bleomycin treatment.