We report 4 clinical cases of hyperammonemic encephalopathy (HE) associated with valproate acid (VPA) and review the literature on its pathophysiology. In all four cases, hepatic function was normal and valproic levels were within the therapeutic range. Elevated ammonium levels were found as the only biochemical abnormality. Patients showed decreased level of consciousness, confusion, ataxia and seizures. In 1 case the EEG showed diffused triphasic waves with frontal predominance. After suppression of treatment with VPA there was remission of clinical manifestations, and ammonium levels returned to normal. In order to obtain the correct diagnosis of HE, in all patients treated with either VPA mono or polytherapy, ammonium levels should be considered.