Therapeutic hypothermia is beneficial to neurological outcome for comatose survivors after out-of-hospital cardiac arrest. However, there are few data of extracorporeal cardiopulmonary resuscitation (ECPR) for induction of hypothermia for patients with out-of-hospital cardiac arrest. We did a prospective study of ECPR with hypothermia for patients with out-of-hospital cardiac arrest. The criteria for inclusion were an age of 18 to 74 years, a witnessed cardiac arrest, collapse-to-patient’s-side interval <15 minutes, cardiac arrest due to presumed cardiac etiology, and persistent cardiac arrest on ER arrival in spite of the prehospital defibrillations. After arrival at the emergency room, cardiopulmonary bypass plus intra-aortic balloon pumping was immediately performed, and then coronary reperfusion therapy during cardiac arrest was added if needed. Mild hypothermia (34°C for 3 days) was immediately induced during cardiac arrest or after return of spontaneous circulation. We selected suitable patients who received conventional CPR with normothermia among a prospective multi-center observational study of patients who had out-of-hospital cardiac arrest in Kanto region of Japan “the SOS-KANTO study” for the control group. The primary endpoint was favorable neurological outcome at the time of hospital discharge. A total of 558 patients were enrolled; 127 received ECPR with hypothermia and 431 received conventional CPR with normothermia. The ECPR with hypothermia group had significantly higher frequency of the favorable neurological outcome than the conventional CPR with normothermia group (12% vs. 2%, unadjusted odds ratio, 8.1; 95% CI; 3.2 to 20.0). The adjusted odds ratio for the favorable neurological outcome after ECPR with hypothermia was 7.4 (95% CI; 2.8 to 19.3, p<0.0001). Among the ECPR with hypothermia group, early attainment of a target core temperature of 34°C increased its efficacy (adjusted odds ratio, 0.99; 95% CI; 0.98 to 1.00, p=0.04). ECPR with hypothermia improved the chance of neurologically intact survival for adult patients with out-of-hospital cardiac arrest, and the early attainment of a target temperature enhanced its efficacy.