Stress-induced gastric mucosal injury is a common clinical entity. On the other hand, abuse of methamphetamine (MA) represents a growing social problem. MA users are frequently in stressful situations. In this study, we examined the effects of MA on gastric injury, corticosterone level and immunomodulation using a water-immersion restraint stress (WRS) mouse model that is well known to induce gastric lesions. Mice were randomly divided into five groups: (1) the normal group, (2) the 3 hour (3 h)-WRS group, (3) the 6 hour (6 h)-WRS group, (4) the MA (3 mg/kg) plus 6 h-WRS group and (5) the MA (30 mg/kg) plus 6h-WRS group. As expected, most animals examined (above 90%) showed gastric injury after the WRS exposure. However, administration of MA at both 3 and 30 mg/kg resulted in significant suppression of the injury. The corticosterone levels were increased by exposure to the stress and/or MA, but there was no difference between these groups. The levels of the serum cytokines IL-6, IL-10 and TNF were increased by WRS, and were markedly increased by MA plus WRS; in particular, the level of IL-6 was synergistically increased. On the contrary, the level of IL-1beta was significantly decreased by WRS and MA plus WRS. This is the first report showing the protective effect of MA on stress-induced gastric injury, although further study is necessary to resolve the mechanism of MA-driven suppression of the injury.