Background: The mechanisms underlying the gender differences in alcohol drinking behavior and alcohol's effects are poorly understood and may reflect gender differences in brain neurochemistry. Alcohol decreases glucose metabolism in the human brain in a pattern that is consistent with its facilitation of GABAergic neurotransmission. We compared the regional changes in brain glucose metabolism during alcohol intoxication between female and male subjects.Methods: Ten female and 10 male healthy controls were scanned with positron emission tomography and 2‐deoxy‐2[18F]fluoro‐d‐glucose twice: 40 min after placebo (diet soda) or alcohol (0.75 g/kg mixed with diet soda).Results: Alcohol significantly and consistently decreased whole‐brain metabolism. The magnitude of these changes was significantly larger in male (−25 ± 6%) than in female (−14 ± 11%;p < 0.005) subjects. Half of the female subjects had reductions in metabolism during intoxication that were significantly lower than those in male subjects. This blunted response in the female subjects was not due to differences in alcohol concentration in plasma, because these did not differ between the genders. In contrast, the self‐reports for the perception of intoxication were significantly greater in female than in male subjects. The cognitive deterioration during alcohol intoxication, although not significant, tended to be worse in female subjects.Conclusions: This study shows a markedly blunted sensitivity to the effects of acute alcohol on brain glucose metabolism in female subjects that may reflect gender differences in alcohol's modulation of GABAergic neurotransmission. The greater behavioral effects of alcohol in female subjects despite the blunted metabolic responses could reflect other effects of alcohol, for which the regional metabolic signal may be hidden within the large decrements in metabolism that occur during alcohol intoxication.