Plasma cyclic AMP levels were determined during a 40 minute secretin infusion (1 Cl.U kg-1h-1) followed by a 40 minute combined secretin (1 Cl.U kg-1h-1) caerulein (75 ng kg-1h-1) infusion. In nine healthy subjects, both secretin alone and secretin in combination with caerulein did not affect plasma cyclic AMP levels. The same was observed in six patients with chronic pancreatitis. By contrast, in patients suffering from liver disease (nine cases) or extrahepatic cholestasis (six cases), secretin elicited large increases in plasma cyclic AMP concentration; the mean values attained being, respectively, seven and four times higher than before the infusion. On the other hand, increases in plasma cyclic AMP 10 minutes after a bolus injection of glucagon (1 mg) were four times lower in the liver disease group as compared to the controls. The results reported here suggest that the liver plays a major role in the degradation of plasma cyclic AMP produced by target tissues responding to secretin, and in the release of cyclic AMP under glucagon. Liver disease reduce the capacity of the liver to clear cyclic AMP from the blood. The pancreas does not contribute significantly to the cyclic AMP in the blood.