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OBJECTIVES: This study sought to compare the cost-effectiveness of a school-based hepatitis B vaccine delivery program with that of a vaccine delivery program associated with a network health maintenance organization (HMO). METHODS: The vaccination program enrolled 3359 sixth-grade students from 18 middle schools in Denver, Colo. Immunization status and direct and indirect program costs were compiled. The sensitivity of the outcomes was assessed by simulation methods. RESULTS: The per-dose cost-effectiveness ratio for the school-based delivery system was $31. This cost-effectiveness ratio remained stable when the model was simulated with costs that were underestimated or overestimated by 20%. In the network HMO, the direct cost per dose was $68 and the societal cost was $118 when the child's father worked full-time and the mother worked part-time. There is less than a 5% chance that the network HMO-based vaccination program could be more cost-effective than the school-based program. CONCLUSIONS: The cost per dose of the school-based program was significantly less than that of the network HMO-based program, because in the school program government-purchased vaccine was available at a lower cost and parents did not incur work-loss costs.