Objective To evaluate the economic impact of the routine US childhood immunization schedule: diphtheria and tetanus toxoids and acellular pertussis; tetanus and diphtheria toxoids; Haemophilus influenzae type b conjugate; inactivated poliovirus; measles, mumps, and rubella; hepatitis B; and varicella vaccines. Design Decision tree–based analysis was conducted using population-based vaccination coverage, published vaccine efficacies, historical data on disease incidence before vaccination, and disease incidence reported for 1995-2001. Costs were estimated using the direct cost and societal (direct and indirect costs) perspectives. Program costs included vaccine, administration, vaccine-associated adverse events, and parent travel and time lost. All costs were inflated to 2001 US dollars, and all costs and benefits in the future were discounted at a 3% annual rate. Participants A hypothetical 2001 US birth cohort of 3 803 295 infants was followed up from birth through death. Main Outcome Measures Net present value (net savings) and benefit-cost ratios of routine immunization. Results Routine childhood immunization with the 7 vaccines was cost saving from the direct cost and societal perspectives, with net savings of $9.9 billion and $43.3 billion, respectively. Without routine vaccination, direct and societal costs of diphtheria, tetanus, pertussis, H influenzae type b, poliomyelitis, measles, mumps, rubella, congenital rubella syndrome, hepatitis B, and varicella would be $12.3 billion and $46.6 billion, respectively. Direct and societal costs for the vaccination program were an estimated $2.3 billion and $2.8 billion, respectively. Direct and societal benefit-cost ratios for routine childhood vaccination were 5.3 and 16.5, respectively. Conclusion Regardless of the perspective, the current routine childhood immunization schedule results in substantial cost savings.