Renal papillary cytoplasmic granularity (RPCG) induced by carbonic anhydrase inhibitors (CAIs) in rats is characterized by the accumulation of dense secondary lysosomes in epithelial, endothelial, and interstitial cells and may be related to drug-induced potassium depletion. Female Sprague-Dawley rats were given the CAI, acetazolamide, by gavage. Half were supplemented with 1% potassium chloride in the drinking water. Two treated groups were allowed to recover for 1 or 2 mo. Potassium supplementation inhibited RPCG by 80% but produced little amelioration of the mild 13% decrease in serum potassium induced by 200 mg/kg/day acetazolamide for 28 days. Acetazolamide-induced RPCG is reversible because 1- and 2-mo recovery periods decreased the incidence by 75% and 80%, respectively. The results support the hypothesis that RPCG is related to potassium depletion secondary to carbonic anhydrase inhibition. Because supplementation of potassium chloride had little effect on serum potassium, these data suggest that depletion of renal medullary potassium content is important in the pathogenesis of RPCG as previously suggested by others. Other types of diuretics that produce hypokalemia as a side effect may not deplete medullary potassium since RPCG has not been reported in humans or animals given these drugs.