Rotavirus is the most common cause of severe diarrhea in children, and a live, oral vaccine may soon be licensed for prevention. To estimate the economic impact of a national rotavirus immunization program in the United States. Cost-effectiveness was analyzed from the perspectives of the health care system and society. A decision tree used estimates of disease burden, costs, vaccine coverage, efficacy, and price obtained from published and unpublished sources. The proposed vaccine would be administered to infants at ages 2, 4, and 6 months as part of the routine schedule of childhood immunizations. Total costs, outcomes prevented, and incremental cost-effectiveness. A routine, universal rotavirus immunization program would prevent 1.08 million cases of diarrhea, avoiding 34000 hospitalizations, 95000 emergency department visits, and 227000 physician visits in the first 5 years of life. At $20 per dose, the program would cost $289 million and realize a net loss of $107 million to the health care system-$103 per case prevented. The program would provide a net savings of $296 million to society. Threshold analysis identified a break-even price per dose of $9 for the health care system and $51 for the societal perspective. Greater disease burden and greater vaccine efficacy and lower vaccine price increased cost-effectiveness. A US rotavirus immunization program would be cost-effective from the perspectives of society and the health care system, although the cost of the immunization program would not be fully offset by the reduction in health care cost of rotavirus diarrhea unless the price fell to $9 per dose.