Protection of the neurological function in post cardiac arrest (CA) patients is still a challenge. Given that cardiac function of post-CA patients can be improved by beta-blocker, namely esmolol. This study examined the effects of esmolol on post-resuscitation induced impairment of nerve function. Ventricular fibrillation (VF) was first induced in pigs (n=24). After 8 min of non-treatment operation, animals received a bolus of esmolol and epinephrine (i.e., S group; 500 mu g/kg and 20 mu g/kg, respectively), epinephrine only (i.e., E group; 20 mu g/kg), or normal saline (i.e., NS group; 1 ml/kg), followed by standard cardiac pulmonary resuscitation (CPR) and defibrillation. Cerebral performance categories (CPC) score was assessed in living pigs. Blood samples and brain tissues were collected for subsequent immunohistochemistry, western blotting, and histopathological examinations, as well as tissue electron microscopy. Esmolol decreased CPC score, improved nerve function, and reduced cerebral edema, as compared with epinephrine only or normal saline treatments. These effects were associated with decreased serum levels of HIF-1 alpha, VEGF, and VEGFR1, and lower Ang-2/Ang-1 in early return of spontaneous circulation (ROSC), and then affects the express in the brain. Smolol relieved the animals' neurologic impairment after ROSC. This might be due to its inhibitory effects on HIF-1 alpha and VEGF systems in early restoration.