I/R injury of the intestine is a life-threatening emergency with mortality rates still more than 60%. We have investigated the protective effect of lamotrigine (LTG), an antiepileptic drug, which has an established neuroprotective effect, on intestinal I/R injury in rats. Forty-eight Wistar albino rats were divided into three groups: a sham-operated group (no I/R injury; n = 16), an ischemic control group (I/R, n = 16), and an LTG-treated group (pretreatment 5 mg kg(-1) LTG + IR; n = 16). A marker for lipid peroxidation, malondialdehyde, free radical scavengers, glutathione peroxidase, catalase, and superoxide dismutase levels, an index of polymorphonuclear neutrophils, myeloperoxidase activity, and mucosal damage were investigated. Malondialdehyde levels, myeloperoxidase activity, and the severity of mucosal damage were decreased in the LTG group. Moreover, in the LTG group, glutathione peroxidase and superoxide dismutase levels were higher compared with the I/R group. The pretreatment of rats with LTG before intestinal ischemia ameliorates the mucosal damage in intestinal I/R injury probably by altering lipid peroxidation, neutrophil accumulation, and antioxidant activity.