Treatment of newborn rat pups with 60 mg/kg‐d chlorphentermine for 7 d produced an accumulation of alveolar foam cells accompanied by an increase in relative pulmonary tissue weight. In contrast, administration of 20 mg/kgd for 1 wk did not markedly alter lung ultrastructure or weight in newborns. Both doses of chlorphentermine elevated the activity of pulmonary aminopyrine N‐demethylase but not that of aniline hydroxylase. The Increase in relative liver weight was associated with stimulation of the activities of aniline hydroxylase and aminopyrine N‐demethylase in newborns administered either chlorphentermine dose. Phenobarbital treatment produced an increase in relative liver weight accompanied by elevated activities of pulmonary aminopyrine N‐demethylase and hepatic aniline hydroxylase and aminopyrine N‐demethylase. Simultaneous barbiturate and chlorphentermine administration produced stimulation in liver enzymes to the same extent as phenobarbital alone. In contrast, phenobarbital potentiated the chlorphentermine‐induced rise in pulmonary aminopyrine H‐demethylase. In the case of 60 mg/kg chlorphentermine and barbiturate, the observed potentiation of lung enzyme activity was associated with a reduction in the number of alveolar foam cells. The results suggest that chlorphentermine and phenobarbital stimulate drug‐metabolizing enzymes in lung and liver of newborn rats and that phenobarbital may provide protection against phospholipidosis through stimulation of pulmonary drug‐metabolizing enzymes.