Islet amyloid polypeptide (IAPP) was identified in human plasma using immunoaffinity chromatography, gel filtration and reverse- phase high performance liquid chromatography coupled with radioimmunoassay specific for the peptide. IAPP[1-37], IAPP[17-37], and other two IAPP- related peptides which were putative pro-IAPPs or different processing products of IAPP, were isolated. All of these IAPPs were also found in human pancreatic extract, indicating that they were secreted from B cell secretory granules into the circulation. IAPP[1-37] is a major molecular form of IAPP in the pancreas, but it accounted for 31% of immunoreactive IAPP in the plasma. Plasma concentration of IAPP in normal individuals increased to 3.0 times the basal level in response to oral administration of 75 g glucose. This study indicated that IAPP is a circulating hormone secreted under glucose stimulation.