The effects of the anorectic drug chlorphentermine (461789) on the composition and stability of alveolar surfactant phospholipids and proteins were studied in Sprague-Dawley-rats. The animals were given daily injections of the drug for either 3 or 10 days. Another group of animals was injected with saline and the same amount of food was given to both groups. Control animals were fed ad lib. The animals were sacrificed, and their alveolar macrophages and alveolar type-II cells were isolated. The incorporation of radiolabeled palmitate, choline and glycerol into disaturated phosphatidylcholines (PC) in both cell types was measured. Total protein was determined, and the proteins were separated on a slab gel by electrophoresis and transferred to nitrocellulose paper. Immunostaining by antibodies to specific surfactant proteins was conducted on the nitrocellulose papers. The antigenic surfactant proteins were quantitated by rocket immunoelectrophoresis. The drug induced increases in surfactant total phospholipids, disaturated PC, and total protein in the lavage, and in surfactant apoprotein on the alveolar surface. Experiments were conducted with labeled substrates of disaturated PC, measuring their incorporation into disaturated PC and release into extracellular spaces. Based on these measurements, the authors conclude that the phospholipidosis does not seem to result from an increase in the synthesis of disaturated PC. The chlorphentermine induced phospholipidosis is believed to be due to decreased rates of phospholipid degradation. The drug may be bound to surfactant phospholipids, making them resistant to pulmonary phospholipases.