Significance Accumulation of islet amyloid polypeptide (IAPP)-containing amyloid fibrils is the main pathological finding in pancreatic islets in type 2 diabetes. The formation of these IAPP amyloid fibrils is considered toxic and may constitute a major cause for the loss of insulin-producing beta cells. The protein domain BRICHOS is present in several different proproteins and possesses antiamyloid chaperone activity. This study demonstrates expression of the BRICHOS-containing protein Bri2 in human pancreatic beta cells and its colocalization with IAPP. The Bri2 BRICHOS domain effectively prevents IAPP from forming fibrils and protects cells from the toxicity associated with IAPP fibrillation. It is concluded that the Bri2 BRICHOS domain may act as an endogenous inhibitor of IAPP amyloid formation in pancreatic beta cells.