OBJECTIVES: A cost-effectiveness analysis on two vaccination programs against rotavirus in Guangzhou, China was conducted for two purposes: 1) a test case in the context of urban areas to enrich the knowledge of national health policy makers in determining the inclusion of these vaccination programs in the Chinese Expanded Programme on Immunization, and 2) the findings may inform the city authorities to include the vaccines in local immunization plans. METHODS: The two interventions under evaluation (through the incremental cost-effectiveness ratio [ICER]) are Lanzhou lamb vaccine and Rotarix. Major costs include those associated with vaccination (prices of vaccines, program costs of implementation, and vaccine wastage) and associated with diarrhea (direct medical costs: outpatient visit and hospitalization; indirect costs: transportation and parents’ loss of wage). Effects were assessed in terms of the number of deaths averted and the number of disability adjusted life years (DALYs) averted. Epidemiological and other parameters are also included. Additionally, 1- and 2-way sensitivity analyses were performed to assess the uncertainty of the base case analysis. RESULTS: The ICER of the Lanzhou lamb vaccine is more than $135,000 per death averted and $4146.16 per DALY averted; the ICER of Rotarix is more than $1.2 million per death averted and $36807.29 per DALY averted. Uncertainty analyses indicate that disease prevalence and the price and efficacy of Rotarix are most influential in determining ICERs. Cost-effectiveness with respect to these leading influential factors was evaluated. CONCLUSIONS: In terms of DALYs averted with respect to the per capita GDP, the Lanzhou lamb vaccine is very cost-effective (ICER < per capita GDP) and Rotarix cost-effective (ICER < 3 times per capita GDP). Two-way sensitivity analyses may also suggest potential competitive pricing strategy for Rotarix in terms of cost-effectiveness. Limitations and generalizability of this study are discussed along with directions for future research.