We compared the effect of valproate (VPA) on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flow (CBF), measured with 18F-2-deoxyglucose (18FDG) and 15O water positron emission tomography (PET), in 10 normal volunteers. Mean VPA dose was 17.7 mg/kg, and mean VPA level was 82.1 mg/L (+/-16.5) for 4 weeks. VPA reduced global CMRGlc by 9.4% (9.60 +/- 0.76 vs. 8.59 +/- 1.02 mg Glc/min/100 g, p < 0.05) and regionally in all anatomic areas (p < 0.05 for 11 of 26 areas). VPA diminished global CBF by 14.9% (56.55 +/- 6.70 vs. 47.48 +/- 4.42 ml/min/100 g, p < 0.002) and regionally in all anatomic areas (p < 0.05 for 12 of 26 areas). No significant correlation was noted between VPA level and either global CMRGlc or CBF. The effect of VPA on global CMRGlc is similar to that of carbamazepine (CBZ) and phenytoin but less than that of phenobarbital, valium, or combination therapy with VPA and CBZ. VPA reduced regional CBF (rCBF) but not CMRGlc in the thalamus, an effect that may be associated with VPA's mechanism of action against generalized seizures.