OBJECTIVES: To determine the cost-effectiveness of providing aspirin, low molecular weight heparin (LMWH), or compression stockings to air travelers for the prevention of air traveler thrombosis (ATT). METHODS: A pharmacoeconomic model was constructed from the perspective of a 1.5 million member US managed care organization (MCO). The model had a one-year time horizon to coincide with typical budgetary cycles. Air travel estimates were calculated using 2005 Federal Aviation Administration and US Census Bureau statistics. Published ATT incidence estimates varied across patient risk factors and distance flown, ranging from zero to 455 events per 100,000 flights. Treatment efficacy estimates for the relative risk reduction of ATT during and immediately following air travel were obtained from published literature. The model assumed prophylactic therapy use prior to each flight; for compression stockings, one set was issued per patient for all flights. Cost inputs included medical charges for incident ATT treatment (extrapolated from the literature) and prophylactic treatments (estimated from wholesale acquisition costs). Five reiterations of the model were performed to test all ATT incidence estimates. Incremental cost-effectiveness ratios (ICERs) were calculated for prophylaxis versus no treatment. RESULTS: In 4 of 5 risk scenarios, ICERs for aspirin prophylaxis was dominant, with potential MCO cost savings ranging from $436,700 to $1,251,500. For compression stockings, ICERs were dominant for patients taking long-haul flights only (>5,000 miles), with potential cost savings of $957,700 to $1,141,600. LMWH prophylaxis did not result in cost savings under any scenario. Reducing the treatment efficacy estimates by up to 20% did not alter these results. CONCLUSION: Payment for prophylactic aspirin therapy for ATT prevention in air travelers resulted in cost savings for a MCO, as did payment for compression stockings for use during long-haul flights. MCOs that develop programs to provide prophylactic therapies to air travelers could realize significant cost savings.