We used positron emission tomography with 18F-2-deoxy-D-glucose to study the effect of carbamazepine on local cerebral metabolic rate for glucose (lCMRGlc) in 9 patients with complex partial seizures. Twenty regions of interest were evaluated. Seven control patients had serial scans without a drug change. Metabolic rates were significantly (p ± 0.05) lower in patients on carbamazepine in 6 of 20 regions of interest (3 left cerebral hemisphere, 3 right). Mean lCMRGlc was 7.4 ± 2.0 mg/min/100 in patients on carbamazepine and 8.8 ± 2.5 in patients off carbamazepine (p < 0.00005; cutoff level for 180 comparisons: 0.00027). The mean (± SEM) difference in 1CMRGlc between scans was 12 ± 2%. No significant changes in lCMRGlc on serial scans were detected in any of the 20 regions for the control group. The mean (± SEM) variation for control regions of interest was 1 ± 1%. This study showed that carbamazepine depresses cerebral glucose metabolism as much as phenytoin does, but much less than phenobarbital does. The difference in effect on lCMRGlc may be related to drug mechanisms of action, as well as to effects on memory, learning, mood, and behavior.