We treated a 31-year-old woman with systemic lupus erythematosus, renal failure with nephrotic syndrome, and a long-standing seizure disorder, who developed severe hyperammonemia with a fatal outcome. Blood chemistry examination did not indicate liver disease, and amino acid concentrations did not suggest a defect in the urea cycle. Discontinuation of anticonvulsant treatment with valproic acid (VPA) failed to bring about improvement. We speculated that hyperammonemia in this case was induced by VPA, and the existence of other underlying factors, including the administration of aspirin and cimetidine, hypoalbuminemia, and renal failure might elevate the concentration of the serum free fraction of VPA.