In this study, we determined the cDNA-predicted amino acid sequence of positions 9-31 of islet amyloid polypeptide from the rabbit and European hare. A synthetic rabbit/hare islet amyloid polypeptide 20-29 peptide was subsequently shown to be strongly fibrillogenic in vitro even though the putative amyloidogenic AILS sequence at positions 25-28 of human and cat islet amyloid polypeptide is modified in the rabbit and hare by a substitution of phenylalanine for leucine at position 27 (i.e. AIFS). Although islet amyloid polypeptide of both the rabbit and hare has an amyloidogenic sequence and is in fact amyloidogenic in vitro, the apparent lack of in vivo islet amyloidosis in rabbits and hares may be related to relatively low levels of islet amyloid polypeptide production by the islet beta cells in these species. This was supported by our findings that there is no substantial immunoreactivity in either rabbit or hare islets, and no measurable amount either in extracts of rabbit pancreases, or in rabbit plasma. This study supports the need for at least two prerequisites for the development of islet amyloidosis in vivo: an inherent fibrillogenic sequence within the islet amyloid polypeptide molecule and an adequate local concentration of islet amyloid polypeptide to promote self aggregation and formation of islet amyloid.