Albino and pigmented strains of rats were administered 0, 5, 25, 100 or 500 mg/kg 2-phenyl-APB-144 by gavage and were killed 14 days later. Although no ocular lesions were found in rats dosed at 5 mg/kg, similar dose-related retinopathy was found at 25, 100, or 500 mg/kg in both albino and pigmented rats. The primary target site appeared to be retinal pigment epithelial (RPE) cells and photoreceptor outer segments (POS). At 25 mg/kg or greater, multifocal retinal detachment with disrupted POS occurred where the RPE cells showed necrotic changes and contact loss with POS due to fragmentation of apical processes in the RPE cells. Also, RPE cells showed hyperplasia, migration, and phagocytic activity toward disrupted POS. The photoreceptor nuclei (outer nuclear cells) were displaced into the areas occupied by disrupted POS. At 100 or 500 mg/kg, multifocal or diffuse disruption of POS and photoreceptor inner segments (PIS) was observed with markedly proliferating RPE cells. The photoreceptor nuclei were disorganized, less numerous, and necrotic. Some photoreceptor nuclei directly apposed the RPE cells or Bruch's membrane due to the absence of both POS and PIS. The cytoplasm of RPE cells was loaded with phagosomes, disrupted lamellar discs, myelin bodies, and lysosomal residual bodies. The morphological changes appeared to be related to lysosomal dysfunction of the RPE cells. The presence of melanin pigment in the RPE cells did not appear to be the primary factor in the development of the retinopathy.