Objective To investigate the effect on electrical restitution of β1-adrenergic receptor antagonist esmolol administered during cardiopulmonary resuscitation in the porcine ventricular fibrillation model. Method Ventricular fibrillation untreated for four minutes was induced by dynamic steady state pacing protocol in 40 healthy male pigs, in which local unipolar electrograms were recorded using one 10-electrode catheter that was sutured to the left ventrieular epicarditan. During CPR, animals were randomized into two groups to receive saline as placebo or esmolol after two standards doses of epinephrine. At postresuscitation 2-hour, six pigs were randomly selected from each group and the second VF induction was performed. Local activation-recovery intervals (ARI) restitutions and the VF inducibility between control group and esmolol group were compared. Western blotting was performed to determine cardiac ryanodine receptor (RyR2) protein expression, and their phosphorylation status. Results No sig-nificant differences were observed at the restoration of spontaneous circulation between two groups. Higher postre-suseitation 2-hour survival rate was observed in the esmolol group. Esmolol significantly flattened ARI restitution slope, lessened regional difference of ARI restitution, decreased the VF inducibility, and alleviated RyR2 hyper-phosphorylation. Conclusions Esmolol given during CPR significantly improved postresuscitation 2-hour survival rate. Its effects on modulating electrical restitution property and intracellular calcium handling make up the most important reasons why β1-blockade significantly reduced the onset and maintenance of VF.