CONTEXT Installation of automated external defibrillators (AEDs) on passenger aircraft has been shown to improve survival of cardiac arrest in that setting, but the cost-effectiveness of such measures has not been proven. OBJECTIVE To examine the costs and effectiveness of several different options for AED deployment in the US commercial air transportation system. DESIGN, SETTING, AND SUBJECTS Decision and cost-effectiveness analysis of a strategy of full deployment on all aircraft as well as several strategies of partial deployment only on larger aircraft, compared with a baseline strategy of no AEDs on aircraft (but training flight attendants in basic life support) for a hypothetical cohort of persons experiencing cardiac arrest aboard US commercial aircraft. Estimates for costs and outcomes were obtained from the medical literature, the Federal Aviation Administration, the Air Transport Association of America, a population-based cohort of Medicare patients, AED manufacturers, and the Bureau of Labor Statistics. MAIN OUTCOME MEASURES Quality-adjusted survival after cardiac arrest; costs of AED deployment on aircraft and of medical care for cardiac arrest survivors. RESULTS Adding AEDs on passenger aircraft with more than 200 passengers would cost $35 300 per quality-adjusted life-year (QALY) gained. Additional AEDs on aircraft with capacities between 100 and 200 persons would cost an additional $40 800 per added QALY compared with deployment on large-capacity aircraft only, and full deployment on all passenger aircraft would cost an additional $94 700 per QALY gained compared with limited deployment on aircraft with capacity greater than 100. Sensitivity analyses indicated that the quality of life, annual mortality rate, and the effectiveness of AEDs in improving survival were the most influential factors in the model. In 85% of Monte Carlo simulations, AED placement on large-capacity aircraft produced cost-effectiveness ratios of less than $50 000 per QALY. CONCLUSION The cost-effectiveness of placing AEDs on commercial aircraft compares favorably with the cost-effectiveness of widely accepted medical interventions and health policy regulations, but is critically dependent on the passenger capacity of the aircraft. Placing AEDs on most US commercial aircraft would meet conventional standards of cost-effectiveness.