Outcome after prehospital defibrillation remains dire. The aim of the present study was to elucidate the pathophysiology of cardiac arrest and to suggest ways to improve outcome. Ventricular fibrillation (VF) was induced in air-ventilated pigs, after which ventilation was withdrawn. After 6.5 min of VF, ventilation with 100% oxygen was initiated. In six pigs (group I), defibrillation was the only treatment carried out. In another six pigs (group II), mechanical chest compression-decompression CPR (mCPR) was carried out for 3.5 min followed by a 40-s hands-off period before defibrillation. If unsuccessful, mCPR was resumed for a further 30 s before a second or a third, 40-s delayed, shock was given. In a final six pigs (group III) mCPR was applied for 3.5 min after which up to three shocks (if needed) were given during on-going mCPR. Return of spontaneous circulation (ROSC) occurred in none of the pigs in group I (0%), in 1 of six pigs in group II (17%) and in five of six pigs in group III (83%). During the first 3 min of VF arterial blood was transported to the venous circulation, with the consequence that the left ventricle emptied and the right ventricle became greatly distended. It took 2 min of mCPR to establish an adequate coronary perfusion pressure, which was lost when the mCPR was interrupted. During 30 s of mCPR coronary perfusion pressure was negative, but a carotid flow of about 25% of basal value was obtained. In this pig model, VF caused venous congestion, an empty left heart, and a greatly distended right heart within 3 min. Adequate heart massage before and during defibrillation greatly improved the likelihood of return of spontaneous circulation (ROSC).