In this study, intrarenal inorganic fluoride concentrations (IR-F) in rabbits were measured after sevoflurane or methoxyflurane anesthesia (SA or MA) to investigate the mechanism of methoxy-flurane nephrotoxicity and to confirm the safety of SA in fluoride nephrotoxicity. At the end of SA of MA, IR-F was 1.5 to 5 times greater in the cortex to papilla region than serum fluoride concentrations (S-F). When S-F were nearly equal, IR-F after MA was not greater than IR-F after SA. IR-F after SA declined rapidly. In contrast, IR-F after MA was maintained at high levels for a protracted period due to the greater solubility of methoxyflurane in fatty tissue. The present study suggests that the most important factor in methoxyflurane nephrotoxicity is the high IR-F of long duration established by urine formation, and that sevoflurane, although it is not associated with fluoride nephrotoxicity under normal conditions, may not be safe when it is used for an extremely long period and at high concentrations.