Background: Vaccination against Lyme disease appears to be safe and effective; however, the cost per quality-adjusted life-year (QALY) gained with vaccination is unknown. Methods: We developed a decision-analytic model to evaluate the cost-effectiveness of vaccination compared with no vaccination in individuals living in endemic areas of Lyme disease. Our analysis encompassed a 10-year time horizon including a 2-year vaccination schedule with an additional year of vaccine effectiveness. The costs and probabilities of vaccination risk, compliance and efficacy, and Lyme disease clinical sequelae and treatment were estimated from the literature. Health-related quality-of-life weights of the various clinical sequelae of Lyme disease infection were obtained from a sample of 105 residents from Nantucket Island, Massachusetts. Results: Vaccinating 10000 residents living in endemic areas with a probability of Lyme disease per season of 0.01 averted 202 cases of Lyme disease during a 10- year period. The additional cost per QALY gained compared with no vaccination was $62300. Vaccination cost $12600/QALY gained for endemic areas with an attack rate of 2.5% per season, and $145 200/QALY gained for an attack rate of 0.5%. Vaccinating individuals over an accelerated 2-month vaccination schedule improved the cost-effectiveness to $53 700/QALY gained. If a yearly booster shot is required for persisting efficacy, the marginal cost-effectiveness ratio increases to $72 700/QALY. The cost-effectiveness of vaccination was most sensitive to the Lyme disease treatment efficacy and assumptions about the persistence of vaccination effect. Conclusion: Vaccination against Lyme disease appears only to be economically attractive for individuals who have a seasonal probability of Borrelia burgdorferi infection of greater than 1%.