Retinal pigment epithelium is known to be engaged in continuous phagocytosis and digestion of old discs of visual cell outer segments, which have a high phospholipid content. The present ultrastructural study was focused mainly on the effects, upon pigment epithelium, of several drugs that are thought to interfere with the enzymatic degradation of phospholipids. Albino rats received high oral doses of chlorphentermine, iprindole, 1-chloroamitriptyline, imipramine, or clomipramine. After treatment for several weeks the pigment epithelial cells were doubled in height due to deposition of excessive amounts of abnormal cytoplasmic inclusions which had a crystalloid substructure. Such inclusions which are known from previous studies to be associated with drug-induced phospholipid storage are suggested to contain nondigestible phospholipids, which in pigment epithelium originate mainly from phagocytosed outer segment discs. The alterations were reversible by withdrawal of the drugs. The functional implications of the epithelial alterations remain to be elucidated. Additional examination of the neuroretina revealed numerous abnormal inclusions, mainly of multilamellated structure. Ganglion cells were affected most. The neuroretinal alterations were reminiscent of those described in human cases of inherited lipidoses.