Dose-response curves for the incidence of coma after intraperitoneal injections of various doses of valproic acid (VP) and octanoic acid (OA) showed that, mole for mole, valproic acid was less toxic than octanoic acid. However, a simultaneous subcoma dose of pentobarbital (PB) enhanced the toxicity of VP more than that of OA. The dose-response curve for NH4Cl was affected by simultaneous subcoma doses of VP and OA but not by PB. VP enhanced the toxicity of the NH4+ by 52%; OA enhanced the toxicity by 12%. PB added significantly to the toxicity of VP and NH4+ when the three were given simultaneously. Doses of 0.7 mmol NH4+ and 0.5 mmol VP given separately had little or no encephalopathic effect, with blood ammonias of 250-1250 micrograms/dl. When given simultaneously they induced a deep coma and raised the blood ammonia threefold, to about 3600 micrograms/dl. Similar doses of OA and NH4+, induced a similar deep coma, but blood levels of ammonia were not as high. Simultaneous injections of 250 mg glucose did not alter the results. Thus VP toxicity is enhanced substantially by its synergistic interactions with PB and the NH4+.