Objective  To evaluate the effect of inhibition of ubiquitin carboxy terminal hydrolase L1 (UCHL1) on cerebral ischemia/reperfusion injury in mice.    Methods  Male BALB/c mice were randomly divided into sham group, ischemia/reperfusion (I/R) group, UCHL1 small interfering RNA (siRNA）group and scramble siRNA (control) group, 10 mice in each group. I/R model was established by reperfusion 24 hours after middle cerebral artery occlusion (MCAO）60 minutes. In the siRNA group and control group, 10 μl UCHL1 siRNA or scramble siRNA was injected into the brain through the lateral ventricle 24 hours before MCAO. The expression of UCHL1 was detected by RT-PCR and Western blotting; the volume of cerebral infarction and the rate of edema were assessed by 2,3,5-triphenyl tetrazolium chloride (TTC) staining; and the score of neurological symptoms was assessed by neurobehavioral scoring.    Results  Compared with the sham group, the level of UCHL1 mRNA and protein in ischemic penumbra of I/R group were significantly higher (P<0.05), while the expression of UCHL1 protein and mRNA in siRNA group were significantly lower (P<0.05); at the same time, the volume of cerebral infarction, edema rate and neurobehavioral damage in I/R group increased significantly, while the volume and edema rate of cerebral infarction and neurobehavioral damage in siRNA group further increased (P<0.05).   Conclusion  Inhibition of UCHL1 can aggravate the cerebral ischemia/reperfusion injury in mice, suggesting that the induction of UCHL1 after MCAO has a protective effect on the cerebral ischemia/reperfusion injury in mice.