BACKGROUND: The liver and renal capsule are the most common site for experimental pancreatic islet transplantation, but it is not optimal. Gastric submucosa space may be an ideal site for islet transplantation; however, whether pro-inflammation factors mediated islet dysfunction could be avoided or alleviated is still unclear. METHODS: Islets of Sprague Dawley (SD) rat were transplanted into the streptozotocin-induced diabetic SD rats. Transplantation sites included gastric submucosa (GS), intraportal vein (PV) and kidney capsule (KC), and the efficiency of glycemic control and site-specific differences of islet grafts were compared. RESULTS: With limited number of islets (800 IEQ) transplanted, improvement of recipient glycometabolism was superior in the GS group. When transplanted with 1200 IEQ islets, the survival of islet grafts were significantly prolonged in the GS group (25.87 ± 4.08 days, compared to 15.97 ± 0.83 days and 17.33 ± 1.41 days in PV and KC groups, respectively, P < .05). Compared with the PV group, the levels of IL-1β and TNF-α were significantly depressed in GS group after 12 h transplantation (15.5 ± 0.70 pg/mL and 13.28 ± 2.80 pg/mL vs. 262.26 ± 53.37 pg/mL and 138.51 ± 39.58 pg/mL, P < .05). CONCLUSIONS: Gastric submucosal would be a potential ideal site for islet transplantation in rat. Gastric submucosal might alleviate the early islet dysfunction triggered by the IL-1β and TNF-α, and which requires a low number of transplanted islets and have a good glycemic control in return.