The amount of amyloid detectable in islets varies, and is not always correlated with degree of beta-cell loss. It has been hypothesized that islet amyloid polypeptide (IAPP) aggregation causes beta-cell dysfunction. In this study, we investigated the relationship between IAPP expression and glucose homeostasis in pancreatectomized patients. Human pancreatic head tissues were collected from 46 pancreatic tumor patients. We divided the diabetic cases into two groups, patients with higher IAPP-expressing islets (DM-H) and patients with lower IAPP-expressing islets (DM-L), and compared both groups to patients with normal glucose tolerance (NGT). Interestingly, oral glucose tolerance test analyses showed that DM-L patients had significantly higher glucose levels and lower C-peptide levels than DM-H patients. Furthermore, the DM-H group showed a relative beta-cell volume similar to that of the NGT group, as well as a significantly higher relative beta-cell volume than the DM-L group. The DM-L group was significantly higher than the DM-H group, not only in the rates of replication and apoptosis, but also in the nuclear C/EBP homologous protein and the ratio of oligomer to IAPP. Thus, IAPP expression may not be an indicator of cell death induction. IAPP, including oligomer, may be an important determinant in the fate of islet beta-cells. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.