Cytoplasmic vacuolation of renal proximal tubular epithelial cells was studied in rats following administration of nitrilotriacetate (NTA) or sucrose. Sucrose was administered at both a high dose (29.2 mmol/kg) and low dose (7.3 mmol/kg) by ip injection. Both levels of sucrose induced severe vacuolation of the renal proximal tubular epithelium, as observed by light microscopy. However, at the high dose, the vacuolation was widespread, affecting essentially all the proximal tubules, while at the low dose, the lesion was distributed in a multifocal pattern. Nitrilotriacetate administered by gavage at a level of 7.3 mmol/kg also induced severe cytoplasmic vacuolation in the renal proximal tubular epithelium. The distribution of this lesion was multifocal and indistinguishable from that caused by the 7.3-mmol/kg dose of sucrose. Electron-microscopic examination of vacuolated tubule cells demonstrated that, in both the NTA- and sucrose-treated animals, the lesion was due to changes in the endocytotic/lysosomal system. The nuclei, mitochondria, golgi and endoplasmic reticulum and the highly convoluted areas of the basal membrane appeared normal in both the vacuolated and non-vacuolated tubule cells of rats given either NTA or sucrose.