We have measured alpha-MSH in plasma of normal subjects and subjects with various diseases of the pituitary-adrenocortical system using a radioimmunoassay with a sensitivity of 1.2 pmol/l. No alpha-MSH could be detected in plasma of normal subjects (n = 6), in plasma of patients with Addison's disease (n = 3), Nelson's syndrome (n = 2), bromocriptine responsive (n = 2) and unresponsive (n = 5) Cushing's disease and in plasma of psychiatric patients on chronic treatment with the dopamine antagonist haloperidol (n = 5). Plasma alpha-MSH remained undetectable in 2 patients with Cushing's disease after iv injection of 60 micrograms/kg haloperidol. In contrast, alpha-MSH was detectable in plasma of normal dogs (n = 2) and dogs with pituitary dependent hyperadrenocorticism (n = 2), whereas the iv injection of halo peridol was associated with a rise of plasma alpha-MSH. Thus we are unable to detect circulating alpha-MSH in man despite the use of a sensitive radioimmunoassay.