Phenylketonuria (PKU) is a metabolic disorder due to variable reduction in activity of the hepatic enzyme phenylalanine hydroxylase (PAH) which causes an accumulation of phenylalanine (Phe). This affects the neurobiology of the brain which, in term, can cause multiple neurological and psychiatric symptoms. Common management involves phenylalanine restriction and supplementation with a Phe-free amino acid mixture. We present the case of a patient with PKU with aggressive behavior with difficulties in pharmacological management of this symptom. The patient was not adherent to dietary restrictions nor pharmacological treatment. Management with valproic acid was tried with development of valproate-induced hyperammonemia. Although there are no studies to support the link between phenylketonuria and valproate-induced hyperammonemia, demyelination and neurotransmitter imbalances caused by phenylketonuria may be factors for the development of valproate-induced hyperammonemia.