Plasma pancreatic glucagon concentrations were determined in the basal state and after the infusion of alanine in 10 patients with acute pancreatitis (5 in an initial episode of pancreatitis), in 10 patients with chronic pancreatic insufficiency, and in 21 healthy controls. In acute pancreatitis, basal glucagon levels were nine times normal but were higher during the initial attack than with a history of previous attacks. The glucagon response to alanine was also increased threefold to fourfold in initial attacks. In contrast, after recovery from the initial attack of acute pancreatitis, during acute episodes of pancreatitis in patients with a history of previous attacks, and in patients with pancreatic insufficiency, alanine failed to elicit a consistent rise in plasma glucagon. The data suggest that hyperglucagonemia may contribute to the hyperglycemia of acute pancreatitis, particularly during the initial episode. Loss of alpha cell responsiveness to alanine provides a sensitive index of previous pancreatitis.