The effect of peripherally administered oxytocin (OT) on gastric ischemia-reperfusion injury (GI-RI) and its possible mechanism were investigated. The Sprague-Dawley (SD) rats were randomly divided into different treatment groups (n = 6). The animal GI-RI model was established by clamping the celiac artery for 30 min to induce ischemia and then released to allow reperfusion for 1 h, and the degree of GI-RI was assessed by scoring the gastric mucosal damage index (GMDI), the gastric fluid output, gastric fluid output, gastric acidity were measured and the surgical preparations of vagotomy and sympathectomy were used to investigate the possible mechanism of OT on GI-RI. The results were as follows. Compared with the control group (NS plus GI-R only, GMDI 121.33±10.40, n = 6), the intra peritoneal (ip) administration of oxytocin (20, 100 μg/0.5 mL) obviously attenuated GI-RI (P<0.05), GMDI were 82.33±14.26, 53.5±5.58 respectively (n = 6); the gastric fluid output and the gastric acidity (evaluated by pH) of the control group were (430.17±87.36) μL, 1.55±0.25 (n = 6), and those of the OT group were (102.45±48.00) μL, 2.65±0.40 (n = 6) res pectively; differences had statistical significance (P<0.01). The effect of oxytocin was reversed by atosiban, a selective oxytocin receptor antagonist. The GMDI of the group given atosiban 10 min before OT was 138.17±24.06 (n = 6), which had no significant difference with the control group. Oxytocin further attenuated GI-RI after vagotomy and sympathectomy (GMDI 6.83±8.89, 29.67±5.54, n = 6), compared with the GI-R group and the oxytocin group (P<0.01). These results indicated that the oxytocin could significantly protect gastric mucosal against injury induced by ischemia-reperfusion, and the oxytocin receptor was involved. This effect of oxytocin may be mediated through the vagus and sympathetic nerve, and then lead to the reduction of gastric juice output and the depression of gastric acidity.