To estimate the economic consequences in the United States of routine childhood immunization of children younger than 1 year of age with a rotavirus (RV) vaccine. Cost-effectiveness analysis of a national RV immunization program from the perspective of the health care system and the perspective of society. Estimates of disease incidence, medical expenditures, productivity costs, vaccine efficacy, and vaccine coverage rates were derived from published literature and unpublished vaccine trial reports. The impact of changes in estimates of vaccine efficacy and medical costs was determined by sensitivity analysis. Incremental cost effectiveness, expressed as savings per case of RV diarrhea prevented. Given a vaccine efficacy rate of 50% and a vaccine cost of $30 per dose, an RV immunization program would prevent more than 1 million cases of RV diarrhea, 58,000 hospitalizations, and 82 deaths per year. A vaccine program would cost $243 million per year but would yield net savings of $79 million from the perspective of the health care system and $466 million from the perspective of society. The incremental cost effectiveness was a savings of $459 per case prevented from the societal perspective and $78 per case prevented from the health care system perspective. Sensitivity analyses substantiated net savings over a wide range of variables, and cost effectiveness increased with greater vaccine efficacy or decreased vaccine cost. Economic and disease reduction benefits would be realized from the use of an RV vaccine that is partially protective against severe RV diarrhea. These findings suggest that immunization with an RV vaccine would be cost effective and cost saving.