To evaluate the pattern of plasma cyclic adenosine 3′,5‵-monophosphate, cyclic guanosine 3‵,5‵-monophosphate, atrial natriuretic factor and glucagon levels in different stages of chronic liver diseases, we measured these variables in 20 normal subjects, 25 patients with genetic hemochromatosis, associated with liver cirrhosis in 19 cases and not in six, eight patients with compensated and 15 with decompensated alcoholic or posthepatitic cirrhosis, and 12 with hepatocellular carcinoma. All variables were within the normal range in non-cirrhotic hemochromatotic patients. Cyclic adenosine 3‵,5‵-monophosphate levels were within the normal range (9.5–15.7 nmol/l) in hemochromatotic cirrhotics and elevated in other patients. Cyclic guanosine 3‵,5‵-monophosphate, atrial natriuretic factor and glucagon were above the normal ranges (1.92–5.91 nmol/l, 8.8–62.7 ng/l, and 39–165 ng/l, respectively) in most patients with cirrhosis both with and without hemochromatosis and in most individuals with hepatocellular carcinoma. Cyclic guanosine 3‵,5‵-monophosphate correlated with atrial natriuretic factor in the former groups but not in the latter. These findings indicate that glucagon and atrial natriuretic factor hypersecretion is an early event in cirrhosis, regardless of its etiology. In hepatocellular carcinoma, the underlying cirrhosis may account for most hormonal and metabolic changes although cyclic guanosine 3‵,5‵-monophosphate increases could also be due to the neoplastic process per se .