The effect of tirilazad mesylate (U-74006F), mannitol, and their combination was investigated on focal cerebral ischemia induced by permanent middle cerebral artery (MCA) occlusion in rabbits. Rabbits were divided into four groups receiving vehicle, U-74006F, mannitol, and U-74006F plus mannitol. Hematocrit (hct), glucose, mean arterial blood pressure (MABP), pH, PCO2, and PO2 were measured both before and after occlusion. Seventy-two hours following the permanent MCA occlusion, the neurological outcome was assessed and a quantitative neuropathologic examination was performed in all rabbits. The neurological outcome was better in the rabbits treated with U-74006F plus mannitol than in the other groups. The size of infarction of the affected hemisphere following MCA occlusion was 49.7% in the control group, 30.6% in the U-74006F group, 47.6% in the mannitol group, and 24.1% in the U-74006F plus mannitol group. There was a statistically significant reduction in infarct size in the U-74006F plus mannitol group compared with the other groups (P<0.05). The ratio of ischemic neurons to total neurons in the cortex was smaller in the U-74006F plus mannitol group than in the other groups. The ratio of ischemic neurons to total neurons in the subcortex was significantly lower in the U-74006F plus mannitol group than in the other groups (P<0.05). Our data provide evidence for the beneficial effects of both U-74006F and U-74006F plus mannitol in promoting neurological recovery and preservation of the ischemic area.