This investigation was designed to determine whether valproic acid (VPA) affects the pharmacodynamics of the depressant action of phenobarbital (PB) and ethanol. Rats received sodium valproate iv, 150 mg/kg, or saline, followed 20 min later by a constant infusion of either PB or ethanol until onset of anesthesia. At that time the concentrations of the depressant drugs in biological fluids were determined. In order to induce anesthesia, VPA‐treated rats required significantly lower PB total serum concentrations (36% reduction) as well as lower PB cerebrospinal fluid concentratioins (20% reduction). Similarly, the ethanol dose required to induce onset of sleep was about 35% lower, and the serum ethanol concentations at that endpoint were 44% lower in the VPA‐treated group as compared to corresponding controls. These results indicate that VPA accentuates the effect of the depresseant action of ethanol and PB on the central nervous system.