BACKGROUND: Rotavirus is the leading cause of severe gastroenteritis in children <5 years of age and is responsible for >500,000 deaths annually; approximately 85% of this burden is in low-income countries eligible for financial support from the GAVI Alliance. We projected the uptake, health impact, and cost-effectiveness of introducing rotavirus vaccination in GAVI-eligible countries to help policy makers in prioritizing resources to gain the greatest health improvements for their constituencies. METHODS: A demand forecast model was used to predict adoption of rotavirus vaccine in the poorest countries in the world. We then modeled health outcomes and direct costs of a hypothetical birth cohort in the target population for scenarios with and without a rotavirus vaccine with use of data on health outcomes of rotavirus infection, vaccine effectiveness, and immunization rates. RESULTS: Vaccination would prevent 2.4 million rotavirus deaths and >82 million disability-adjusted life-years (DALYs) in 64 of the 72 GAVI-eligible countries introducing vaccine from 2007 through 2025. The cost per DALY averted decreases over time, from a high of US$450 per DALY averted in the first year to a sustained low of $30 per DALY during 2017-2025, with a cumulative figure of $43 per DALY averted during 2008-2025. By applying the baseline scenario with an initial vaccine price of $7 per dose for a 2-dose vaccine, with a gradual decrease beginning in 2012 and stabilizing at $1.25 per dose by 2017, vaccination was very cost-effective in all GAVI-eligible countries with use of each country's gross domestic product per DALY averted as a threshold. CONCLUSIONS: Introduction of rotavirus vaccines into the world's poorest countries is very cost-effective and is projected to substantially reduce childhood mortality.