Abstract Diphenylhydantoin is one of the most widely used anticonvulsant agents in humans. To examine its effects on brain metabolism, we used the quantitative autoradiographic [ 14C]deoxyglucose method to measure local cerebral glucose utilization in adult rats receiving 50 mg/kg/day diphenylhydantoin for 1 week. Thirty-three brain structures were analyzed to determine whether the drug has global or site-specific effects on cerebral metabolism. Chronic administration produced statistically significant decreases in 23 neocortical and subcortical structures compared with those in vehicle-injected control animals. Therefore, our data support the concept that diphenylhydantoin has widespread depressant effects on brain metabolism.