We have examined the hypothesis that insulin insensitivity in hepatic cirrhosis is related to abnormalities of glycogen deposition and skeletal muscle enzyme activities. Otherwise well patients with biopsy-proven hepatic cirrhosis secondary to previous excess alcohol intake were studied. Prior to study, in basal state, patients had identical blood glucose concentrations but raised serum insulin concentrations (cirrhotic: 8.5 ± 0.8 mU per liter; matched control subjects: 5.7 ± 0.5 mU per liter, p < 0.01). Muscle glycogen content, glycogen synthase activity and pyruvate dehydrogenase activity were normal in the basal state. The cirrhotic patients required less glucose to maintain the clamp in response to 0.1 unit per kg per hr insulin (6.7 ± 0.5 vs. control 8.3 ± 0.4 mg per kg per min, p < 0.05) and deposited less glycogen in muscle during the clamp (8.6 ± 0.5 vs. 12.0 ± 1.4 mg per gm protein, p < 0.05). Glycogen deposition correlated with clamp glucose requirement in the cirrhotic patients (r = 0.78, p < 0.05). The expressed activity of glycogen synthase activity was significantly lower in cirrhotic patients at the end of the clamp (26.5 ± 1.1% vs. 30.9 ± 1.6%) and again correlated with clamp glucose requirement (r = 0.82, p < 0.05). Skeletal muscle pyruvate dehydrogenase activity was not different in patients and control subjects. Insulin insensitivity in hepatic cirrhosis appears to be related to abnormalities of glucose deposition as glycogen in skeletal muscle.