As many as 1000 lives are lost annually from cardiac arrest in commercial aircraft. Ventricular fibrillation (VF), the most common mechanism, can be treated effectively only with prompt defibrillation, whereas the current policy of most airlines is to continue cardiopulmonary resuscitation pending aircraft diversion. The objective of this study was to assess the impact of making semiautomatic external defibrillators (AEDs) available for use on airline passengers with cardiac arrest. AEDs were installed on international Qantas aircraft and at major terminals, selected crew were trained in their use, and all crew members were trained in cardiopulmonary resuscitation. Supervision was provided by medical volunteers or (remotely) by airline physicians. During a 64-month period, AEDs were used on 109 occasions: 63 times for monitoring an acutely ill passenger and 46 times for cardiac arrest. Twenty-seven episodes of cardiac arrest occurred in aircraft, often (11 of 27 [41%]) unwitnessed, and they were usually (21 of 27 [78%]) associated with asystole or pulseless idioventricular rhythm. All 19 arrests in terminals were witnessed; VF was present in 17 (89%). Overall, defibrillation was initially successful in 21 of 23 cases (91%). Long-term survival from VF was achieved in 26% (2 of 6 in aircraft and 4 of 17 in terminals). The ability to monitor cardiac rhythm aided decisions on diversion, which was avoided in most passengers with asystole or idioventricular rhythm. AEDs in aircraft and terminals, with appropriate crew training, are helpful in the management of cardiac emergencies. Survival from VF is practicable and is comparable with the most effective prehospital ambulance emergency services. Costly aircraft diversions can be avoided in clearly futile situations, enhancing the cost-effectiveness of the program.