Treatment of newborns with 20 mg/kg/day chlorphentermine orally for 1 week increased incorporation of thymidine into lung DNA without an associated change in tissue morphology or cyclic AMP levels. An increase in chlorphentermine dose to 60 mg/kg resulted in an accumulation of alveolar hypertrophic macrophages and a rise in incorporation of thymidine into lung DNA; however, cyclic AMP levels were decreased. In contrast, 20 or 60 mg/kg/day for 1 week phentermine-induced depression in the incorporation of thymidine into pulmonary DNA was accompanied by a decrease in cyclic AMP but no apparent alteration in tissue morphology. Hyperoxia did not modify the phentermine-induced changes in cyclic AMP levels and pulmonary ultrastructure. In contrast, hyperoxia altered the responsiveness of newborns to 20 mg/kg chlorphentermine as evidenced by the presence of foam cells. Data suggest that the chlorphentermine-induced increase in DNA synthesis in newborn lung seems independent of changes in cyclic AMP and tha modification of drug-induced alterations by hyperoxia may be related to the chemical structure of a compound.