The possibility that the metabolism of volatile inhalational anesthetics is altered following chronic ethanol consumption was investigated in male Fischer 344 rats. The hepatic microsomal defluorination rates of methoxyflurane, enflurane, and sevoflurane were determined for pair-fed rats receiving ethanol with normal caloric or with 50% of normal caloric intake. For comparison, the effects of phenobarbital treatment on anesthetic defluorination rates also were examined. Fourteen days of ad libitum consumption of 16% ethanol resulted in maximal defluorination rates of the above anesthetics. No overt signs of ethanol toxicity were observed. Ethanol-treated rats with a normal caloric intake had significantly increased microsomal defluorination rates per mg protein compared with pair-fed control rats as follows: methoxyflurane, 190% of control; enflurane, 298% of control; and sevoflurane, 301% of control. Ethanol-treated animals with 50% of normal caloric intake showed similar elevations in microsomal defluorination rates when compared with pair-fed controls. Phenobarbital treatment significantly increased the rate of methoxyflurane defluorination (673% of control), whereas the rates of sevoflurane defluorination (127% of control) and enflurane defluorination (86% of control) were not altered significantly. Phenobarbital treatment increased the microsomal content of cytochrome P-450, while ethanol treatment did not. This study demonstrated that regardless of total caloric intake, chronic ethanol consumption increases defluorination of inhalation anesthetics in Fischer 344 rats. It also illustrated that the two enzyme-inducing agents are unique with respect to the degree to which they enhance anesthetic defluorination.