Background: Recent experimental and clinical studies have indicated that the β-adrenergic effect of epinephrine significantly increases the severity of post resuscitation myocardial dysfunction.The aim of the study was to investigate whether the short-acting β1-selective adrenergic blocking agent, esmolol, would attenuate post resuscitation myocardial dysfunction in a porcine model of cardiac arrest.Methods and Results: After 8 min of untreated ventricular fibrillation and 2 min of basic life support, 24 pigs were randomized to three groups (n =8 per group), which received central venous injection of either epinephrine combined with esmolol (EE group), epinephrine (EP group), or saline (SA group).Hemodynamic status and blood samples were obtained at 0, 30, 60, 120, 240 and 360 min after return of spontaneous circulation (ROSC).Surviving pigs were euthanatized at 24 h after ROSC, and the hearts were removed for analysis by electron microscopy, Western blotting, quantitative real-time polymerase chain reaction, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay.Compared with the EP and SA groups, EE group had a better outcome in hemodynamic function, (improved dP/dt maxima and minima and cardiac output) (P <0.05), and improved oxygen metabolism (oxygen delivery and oxygen consumption) (P <0.05), which suggesting that EE can protect myocardial tissue from injury and improve post-resuscitation myocardial dysfunction.The protective effect of EE also correlated with reducing cardiomyocyte apoptosis, evidenced by reducing TUNEL-positive cells, increasing anti-apoptotic Bcl-2/Bax ratio and suppression of caspase-3 activity in myocardium.Conclusion: Esmolol, a short-acting β1-selective adrenergic blocking agent, given during CPR has significant effects on attenuating post resuscitation myocardial dysfunction.The current study provides a potential pharmacologic target for post resuscitation myocardial dysfunction.