This study was designed to determine the nephrotoxic potential of prolonged anesthesia with enflnrane or isoflurane in obese and nonobese Fischer 344 rats. Weight-paired rats received either a regular chow diet or Potter's high fat diet for 16 weeks. The chow-fed (nonobese) rats gained 20% in body weight compared with 45% for the Potter's-fed (obese) rats. Exposure of nine pairs of rats to 2.0% enflurane for 4 h resulted in significantly elevated peak serum F levels (62 ± 11 μMvs.27 ± 6 μM;P< 0.001) in obese compared with nonobese rats and clinical signs of F−-induced nephrotoxicity (i.e., polyuria) confirmed by decreased creatinine and urea nitrogen clearances in the obese rats. Exposure of nine pairs of rats to 1.4% isoflurane for 4 h produced significantly elevated peak serum F−levels (27 ± 8 μMvs.9 ± 0.4 μM;P< 0.001) in obese compared with nonobese rats and subclinical nephrotoxicity in obese rats manifested by significantly decreased creatinine and urea nitrogen clearances, but without polyuria. This study suggests that obese patients may be at risk of developing F−-induced nephrotoxicity following prolonged enflurane anesthesia. Isoflurane may have significant potential for subclinical F−-induced nephrotoxicity in obese patients, to a degree that might affect renal clearance of some drugs in the postoperative period.