In this study, the effect of naloxone and mannitol was investigated on focal cerebral ischemia induced by middle cerebral artery occlusion with the transorbital approach in the rabbit model. Rabbits were randomly and blindly assigned to one of three groups (six animals in each): (1) a control group that received equal volumes of physiological saline solution; (2) a naloxone group that received a 5 mg/kg bolus of naloxone i.v. 1 h after occlusion, followed by 2 mg/kg per hour i.v. infusion for 5 h; (3) a mannitol group that received 0.2 g/kg twice with an interval of 10 min at 5 h. The neurological outcome was better in rabbits treated with naloxone than in the others. The ratio of ischemic to total neurons in the cortex was smaller in the naloxone group than in the control and mannitol groups (P<0.05). In addition, there was a statistically significance reduction in infarct size in the naloxone group compared with the other groups (P<0.05). Edema was severe in the control and mannitol groups, but moderate in the naloxone group. There was no statistically significant difference in Na+, K+, and water content between groups. Our data provide evidence for the beneficial effects of naloxone on promoting neurological recovery and preserving the ischemic area.