To determine the frequency of hyperammonemia in asymptomatic patients receiving valproic acid, plasma ammonia concentrations were measured in 55 patients receiving this drug and in 12 patients receiving other anticonvulsants. Twenty-nine of the 55 patients receiving valproic acid and none of the control patients had plasma NH3 levels above the normal range. Ten of the 11 patients receiving both valproic acid and phenytoin sodium in combination had elevated NH3 levels, as did five of six patients receiving both valproic acid and phenobarbital sodium. Elevations in plasma NH3 levels, as high as 140 mumole/L, were well tolerated, and valproic acid dose reductions were not necessary. Based on our findings, hyperammonemia is not an indication for reducing or eliminating valproic acid therapy.