Abstract Objective Post-resuscitation myocardial dysfunction is a major cause of fatality in patients receiving successful cardiopulmonary resuscitation. The mechanism of post-resuscitation myocardial dysfunction is largely unknown, although is generally considered related to ischaemia occurring during cardiac arrest and resuscitation and/or reperfusion injury after restoration of circulation. A key mechanism responsible for reduced contractile reserves in chronic heart failure is impaired β-adrenergic receptor signalling. Thus, we hypothesised that β-adrenergic receptor signalling is markedly abnormal in the post-resuscitation period following cardiopulmonary resuscitation. Methods Male landrace domestic pigs were randomised into a sham group (anaesthetised and instrumented, no ventricular fibrillation) or cardiopulmonary resuscitation (CPR) group (ventricular fibrillation) (n=8 per group). Haemodynamic and echocardiographic data were recorded. β-Adrenergic receptor signalling was assessed at 6h after the operation by measuring myocardial adenylate cyclase activity, β-adrenergic receptor density and β-adrenergic receptor kinase expression. Results Left ventricular function in the CPR group was significantly decreased at 6h after restoration of spontaneous circulation. Basal and isoproterenol-stimulated adenylate cyclase activity was blunted in the CPR group compared with the sham group. Total β-AR density was significantly decreased in CPR group compared with the sham group. Myocardial β-adrenergic receptor kinase expression was 2.03-fold greater in the CPR group than in the sham group. Conclusions β-Adrenergic receptor signalling is markedly impaired in the post-resuscitation period, which may be a mechanism of post-resuscitation myocardial dysfunction.