Fourteen normal controls, eleven patients with non-alcoholic cirrhosis, twenty-nine with hepatocellular carcinoma (HCC) and six with HCC and hypoglycemia were studied. The tests performed include iv glucose tolerance test (25 g) and glucagon challenge test (2 mg). In cirrhosis, glucose intolerance and insulin resistance were demonstrated. The fasting hyperinsulinemia in cirrhosis is the result of decreased degradation as shown by the normal fasting C-peptide. The increased insulin responses to glucose, despite a normal C-peptide response, further supports the importance of impaired degradation in the pathogenesis of hyperinsulinemia after challenge. Despite a strong etiological association between cirrhosis and HCC, patients with HCC do not have significant hyperinsulinemia or glucose intolerance. This provides metabolic evidence to support the clinico-pathological observation that HCC patients with clinically overt hypoglycemia, the fasting glucose, insulin and C-peptide were very low. the C-peptide responses to glucose and glucagon challenges were suppressed despite pharmacologic stimulation. this can be explained by the suppression of insulin secretion by a circulating substance secreted by heptoma. the results support the pathogenetic importance of insulinlike activities recently detected in HCC patients with hypoglycemia.