The renal excretion and certain pharmacokinetic properties of cimetidine were studied in anesthetized rats undergoing moderate osmotic diuresis. When cimetidine concentrations in plasma (Pcim) were low, ca. 2 micrograms/ml, the clearance of cimetidine (Ccim) was 2.64-fold greater than the glomerular filtration rate (GFR). Ccim was lower at higher concentrations, e.g., at ca. 200 micrograms/ml, Ccim/GFR was 1.24. When animals with low Pcim were alkalotic (bicarbonate infusion), Ccim/GFR was 1.82 (different from control, P less than 0.01). In nonalkalotic animals, Ccim/GFR was not influenced by changes in urine flow rate. High levels of Pcim completely blocked net secretion of the cation, tetraethylammonium ion, but did not inhibit the secretion of the anion p-aminohippurate. The half-time of cimetidine in plasma was 43 to 49 min. The apparent volume of distribution was 3.6-fold greater than estimated total body water. We conclude that cimetidine is secreted by the renal organic cation transport mechanism and that it probably undergoes passive reabsorption (nonionic diffusion) to a modest extent when the urine is alkaline. The relatively long half-life of the drug in the body, despite its very high renal clearance, is attributable to the large volume of distribution.