Pipecolic acid is regarded as a γ-aminobutyric acid receptor agonist. Stereochemical studies of pipecolic acid were performed in patients with chronic liver diseases. Plasma d- and l-pipecolic acid were significantly elevated in 15 liver cirrhotic patients with no history of hepatic encephalopathy (1.05+/-0.24 μmol/l, 1.58+/-0.13 μmol/l, p<0.01) and in 27 patients with chronic hepatic encephalopathy (1.58+/-0.50 μmol/l, 2.38+/-0.58 μmol/l, p<0.001) compared to 15 normal subjects. In seven patients with chronic hepatic encephalopathy orally treated with kanamycin, plasma pipecolic acid significantly decreased (d-acid: before 1.62+/-0.23 μmol/l, after 0.61+/-0.15 μmol/l; p<0.01, l-acid: before 2.43+/-0.52 μmol/l, after 2.23+/-0.11 μmol/l; p<0.05). These results suggest that plasma pipecolic acid, particularly d-acid, is produced from d-lysine by intestinal bacteria in liver cirrhotic patients and that pipecolic acid could be involved in the pathogenesis of hepatic encephalopathy.