During concurrent administration of phenobarbital and valproic acid, phenobarbital plasma concentrations often increase. This often requires a reduction of phenobarbital dosage. In normal cats and patients with epilepsy, we found no evidence of decreased renal excretion of phenobarbital. Metabolic studies in four patients revealed a decrease in the conversion of phenobarbital to hydroxyphenylphenobarbital and decreased urinary ratios of hydroxyphenylphenobarbital to phenobarbital. These data suggest that phenobarbital metabolism is inhibited by therapeutic plasma levels of valproic acid.