We report new information on the presence of alpha-melanotropin(alpha-MSH)-like immunoreactivity in the peripheral circulation of the adult human. Pooled blood from 20 patients with non-endocrine diseases was subjected to a Sep-pak pre-purification followed by a high pressure liquid chromatographic (HPLC) fractionation. The eluate from the HPLC column was analyzed by a radioimmunoassay (RIA) specific for the C-terminal part of the alpha-MSH molecule. From this it appeared that alpha-MSH was the major alpha-MSH-like immunoreactive peptide present in human blood with a level of 2-5 pg/ml. This level is similar to the one determined by direct measurements in Sep-pak pre-purified human plasma (median 2.0 pg/ml, n = 11). Des-acetyl alpha-MSH was present in human blood in only a minor quantity. We discuss this finding in view of earlier reports on alpha-MSH-like immunoreactivity in human pituitary tissue.