OBJECTIVES: To conduct a cost-effectiveness analysis of a universal childhood hepatitis A vaccination program in Brazilian regions with different hepatitis A endemicity. METHODS: An age and time-dependent dynamic model was developed to estimate the incidence of hepatitis A for 24 years. The analysis was run separately, according to the pattern of regional endemicity, one for Southern + Southeast (low endemicity) and one for the North + Northeast + Midwest (intermediate endemicity). The decision analysis model compared universal childhood vaccination with current program of vaccinating high risk individuals. Epidemiologic and cost estimates were based on data retrieved from a nationwide seroepidemiological survey for viral hepatitis, primary data collection, National Health Information Systems and literature. The analysis was conducted from the healthcare system and societal perspectives. Costs are expressed in 2008 Brazilian reals. RESULTS: In this model a universal national immunization program would have a significant impact on disease epidemiology in all regions, resulting in 64% reduction in the number of cases of icteric hepatitis, 59% reduction in deaths due to disease and a 62 % decrease of life years lost, in a national perspective. With a vaccine price per dose of R$16.89 (US$7.23), vaccination against hepatitis A was a cost-saving strategy in the low and intermediate endemicity regions and in Brazil as a whole from healthcare and society perspective. Results were most sensitive to icteric hepatitis incidence, ambulatory cases and vaccine costs. CONCLUSIONS: Universal childhood vaccination program against hepatitis A could be a cost-saving strategy in all regions of Brazil. These results may be useful for the Brazilian government for vaccine related decisions and for monitoring population impact if the vaccine is included in the National Immunization Program.