The effect of a single, intravenously administered dose of glucagon on plasma cyclic adenoside monophosphate (cAMP) was studied in seven normal subjects, ten patients with chronic renal failure (CRF), and ten patients with terminal renal insufficiency (TRI) receiving long-term haemodialysis treatment (HD). Ten minutes following glucagon administration, uremic patients displayed a significantly (P less than 0.0001) greater increase in cAMP than control subjects. Glucose levels after glucagon administration did not differ significantly between the normal and uremic groups, and lipolysis was less pronounced in the uremic patients than in the controls (P less than 0.003). These results could not be attributed to differences in serum insulin response. The findings demonstrate differences in the hepatic adenylate cyclase and cAMP response between normal and uremic subjects. These alterations in cAMP responsiveness may play a role in the pathophysiology of the metabolic disturbances associated with uremia.