Histological, histochemical, and ultrastructural examinations were performed on pulmonary and hepatic tissues of rats after prolonged oral treatment with several tricyclic antidepressants and two neuroleptics, which are all of amphiphilic character. The antidepressants ipindole, imipramine, clomipramine, 1-chloro-amitriptyline, and 1-chloro-10,11-dehydro-amitriptyline were found to cause an accumulation of intraalveolar foam cells accompanied by the formation of abnormal lamellated and crystalloid cytoplasmic inclusions in most pulmonary and hepatic cell types. The ultrastructural and histochemical findings in both tissues point to generalized, abnormal intracellular storage of polar lipids, i.e. to drug-induced lipidosis. The foam cells are not regarded as an isolated pulmonary alteration but rather as an easily obtainable indication of generalized lipidosis, under the present conditions. They are thought to represent alveolar macrophages stuffed with non-digestible phospholipids. On the other hand, the tricyclic antidepressants noxiptiline and amitriptyline, and the neuroleptics chlorpromazine and thioridazine caused neither formation of foam cells nor of any lipidosis-like ultrastructural alterations. These negative results are tentatively ascribed to a more rapid biotransformation of the amphiphilic drug molecules into more hydrophilic metabolites which no longer have a high affinity to polar lipids. Two main conclusions can be drawn from the present ovservations: (1) Intraalveolar foam cells must not be regarded as a fortuitous alteration but rather as a first indication of generalized phospholipidosis, when they are found in animals treated with an amphiphilic drug. (2) Closely related compounds of amphiphilic character do not necessarily have the same potency to induce a phospholipidosis under in vivo conditions.