The present study investigated the effect of Z-Ligustilide (LIG), a characterized 3-n-alkyphthalide derivative existed in many medical Umbelliferae plants, on permanent focal ischemic brain injury in rats. Focal cerebral ischemia was induced by the occlusion of middle cerebral artery (MCA) for 24 h. LIG (20, or 80 mg/kg), orally administered at 2 h after ischemia, reduced the cerebral infarct volumes by 48.29% and 84.87% respectively compared to control group as visualized by 2,3,5-triphenyltetrazolium chloride (TTC) staining (p<0.01). Treatment with LIG could dose-dependently reduce brain swelling by 68.62% and 82.08% (p<0.01), and significantly improve behavioral deficits (p<0.01). In addition, LIG at the above used doses had no significant effect on rat body temperature. These data, along with previous findings in our lab demonstrating the neuroprotective effects of LIG in transient cerebral ischemia, suggest that LIG may be a potential neuroprotective agent for the treatment of ischemic stroke in future.