We repeatedly measured blood-brain barrier passage of phenylalanine, leucine, glucose and GABA in nine patients with hepatic encephalopathy using the intravenous double-indicator technique. Controls were four patients without liver disease and two of the patients who had recovered completely from their hepatic encephalopathy. The corrected cerebral venous output curves were fitted by use of a three-compartment model with four parameters. In the patients with hepatic encephalopathy, the permeability-surface area products for phenylalanine and leucine from the blood to the brain and from the brain interstitial fluid to the intracellular compartment, the unidirectional extraction and the brain amino acid influx were similar in the two groups. The permeability from the brain back to blood for phenylalanine was decreased by 72% in patients with hepatic encephalopathy compared with that in the control group (p < 0.05), whereas no difference was seen for leucine. The permeability from the brain back to the blood for phenylalanine decreased with coma grade and normalized in the two patients who recovered. Correspondingly, the calculated brain interstitial fluid concentration of phenylalanine was increased in the patients with hepatic encephalopathy. The transfer variables for blood-brain barrier passage of glucose were similar in the two groups. The permeability from the blood to the brain for GABA was very low in both the patients with hepatic encephalopathy and the control group. We conclude that in hepatic encephalopathy the permeability from brain to blood for phenylalanine decreases with coma grade. The decrease is caused by an increased interstitial fluid concentration of the amino acid. No evidence was found of general or selective blood-brain barrier disturbance in hepatic encephalopathy.