Daily, intraperitoneal administration of the anorectic drug chlorphentermine (30 mg/kg) for 5 days to rats significantly increased phosphatidylcholine and total phospholipid content after 1 week and reached a maximal level 4 weeks after treatment in whole lung tissue (unlavaged lungs) and in sessile tissue in which alveolar lipids and macrophages were removed by pulmonary lavage (lavaged lungs). In lavaged lung, a significant rise in the content of sphingomyelin, phosphatidylserine plus phosphatidylinositol component, and phosphatidylethanolamine plus phosphatidylglycerol fraction occurred after 2 weeks, remained at this increased level for 4 weeks, and was followed by a return to control amounts after 5 weeks. In unlavaged lung, the chlorphentermine-induced elevation in sphingomyelin content seen after 1 week persisted at this same significant level even 5 weeks after treatment. Regardless of experimental duration, pulmonary glycogen levels were not altered markedly by chlorphentermine in unlavaged or lavaged tissue. Phenobarbital (30 mg/kg) did not markedly alter pulmonary glycogen and phospholipid component levels. Simultaneous phenobarbital and anorectic drug administration prevented the chlorphentermine-induced rise in total phospholipid, sphingomyelin, and phosphatidylcholine in unlavaged lung without a change in glycogen. A 7-day withdrawal from chlorphentermine treatment in rats previously injected with drug for 2 weeks resulted in a return to control in the levels of sphingomyelin, phosphatidylcholine, and total phospholipid in unlavaged lung. Extension of withdrawal from treatment for 2 weeks produced a significant decrease in all phospholipid components below control values, suggesting that a possible imbalance in synthetic and catabolic activity may persist after drug removal. The concentration of lung glycogen was not altered significantly by chlorphentermine treatment or withdrawal from drug administration. Our results indicate that the chlorphentermine-induced rise in phospholipid components was time-dependent in lavaged and unlavaged lungs, and the increase in phosphatidylcholine occurred independently of a change in glycogen. In addition, the present study shows that the chlorphentermine-induced changes in phospholipid levels are reversible and almost completely prevented by phenobarbital.