The fasting plasma level of reduced glutathione (GSH), a methionine-derived tripeptide, is reduced in cirrhosis. There is evidence that a reduced activity of S-adenosyl-L-methionine synthetase limiting the flux of methionine along the transmethylation/transsulfuration pathway may contribute to decrease GSH levels. No studies have analyzed plasma GSH in response to a methionine load. In 6 control subjects and in 10 patients with cirrhosis, plasma sulfur amino acid and plasma and erythrocyte GSH levels were measured in response to a L-methionine load (0.1 g/kg). Blood samples were obtained throughout the day after the oral load. Urine was collected for measurement of sulfur excretion. During the study period, all subjects consumed a standard diet of 1,683 kcal containing 2% protein and virtually no methionine. Plasma methionine increased in both groups to a peak level exceeding 20 times the basal value 90 minutes after the load, and declined thereafter. Methionine clearance, calculated on the descending part of the methionine-time curve, was reduced by 50% in cirrhosis (P = .0001). Fasting GSH was higher in controls (mean +/- SD, 3.9 +/- 1.3 v 1.6 +/- 0.7 micromol/L, P = .0004). In response to a methionine load, it peaked at 10.2 +/- 7.2 and 3.2 +/- 1.3 micromol/L, respectively (P = .009). Thereafter, plasma GSH progressively declined, and after 24 hours, it returned to the fasting preinfusion values in both groups. Plasma cysteine and taurine concentrations, as well as the erythrocyte GSH time course, paralleled plasma GSH levels, with less significant differences between groups. Sulfate excretion was delayed. GSH synthesis is stimulated by a methionine load. The reduced flux of methionine along the transmethylation/transsulfuration pathway reduces GSH synthesis in cirrhosis. Defective methionine metabolism also may be responsible for reduced fasting GSH.