In normal subjects, ingestion of tyrosine or phenylalanine stimulates prolactin (PRL) secretion. In patients with phenylketonuria (PKU), we found normal PRL responses to phenylalanine, demonstrating that conversion of phenylalanine to tyrosine is not necessary for PRL stimulation. PKU patients also showed greater PRL responses to tyrosine during dietary phenylalanine restriction than when consuming an unrestricted diet; this finding is consistent with inhibition by phenylalanine of tyrosine transport across the blood-brain barrier. Such competitive inhibition of a normal brain function may serve as a model for some of the neurotoxic effects of phenylalanine in PKU.