In this study, the effects of autologous islet transplantation (ITx) were compared to those of oral antidiabetic drugs (OAD) after distal pancreatectomy (NCT01922492). We enrolled nondiabetic patients who underwent distal pancreatectomy for benign tumors. In the ITx group, islets were isolated from the normal part of the resected pancreas and implanted via the portal vein. Patients who did not receive ITx were regularly monitored and were enrolled in the OAD group if diabetes mellitus developed. The OAD group was treated with metformin with or without vildagliptin. Metabolic parameters were monitored for 12 months postoperatively. Nine patients in the ITx group and 10 in the OAD group were included in the analysis. After 12 months, hemoglobin A1c significantly increased by 5% of the baseline in each group. Area under the curve for blood glucose (AUCglucose) of the 75-g oral glucose tolerance test increased similarly in the immediate postoperative period in both groups but significantly reduced only in the ITx group thereafter. Insulinogenic index (INSindex) significantly decreased from 25.6 ± 18.9 to 4.7 ± 3.7 in the OAD group, while no significant change was observed in the ITx group (from 15.0 ± 4.5 to 11.0 ± 8.2). In the multiple regression analysis, ITx was an independent factor for changes in AUCglucose and INSindex. In addition, changes in INSindex in the ITx group after postoperative 6 months were associated with the efficacy of islet isolation, amount of grafts, and peak serum HMGB1 and VEGF levels after ITx. ITx was superior to OAD in maintaining insulin secretory capacity and glucose tolerance after distal pancreatectomy.