OBJECTIVES: To evaluate the projected health outcomes, costs, and cost-effectiveness of universal mass vaccination (UMV) with RotarixTM (GlaxoSmithKline) in Canada compared with no vaccination. METHODS: An age-compartmental, deterministic, static Markov cohort model was developed to simulate the disease process of acute diarrhea events caused by rotavirus infection up to the age of 5 years in ‘monthly’ time cycles, using Canadian demographic and epidemiology data.  The base-case analysis was performed to estimate the direct effects of a UMV program with two doses of RotarixTM at 2 and 4 months of age compared to no vaccination, assuming 90% vaccination coverage. Costs and utilities were discounted at 3.5%. The efficacy of RotarixTM was based on published clinical trial results. Model outputs include clinical endpoints (deaths, hospitalizations, emergency department (ED) visits and outpatient visits), and economic measures (net costs per case/death prevented and quality-adjusted life year gained). Incremental cost-effectiveness ratios (ICERs) were calculated from the healthcare system perspective, and productivity loss was reported separately. One-way sensitivity analysis was performed to evaluate the robustness of the model to variations in the underlying input parameters. RESULTS: Without vaccination, a Canadian birth cohort of 380,000 can be expected to have 152,000 rotavirus diarrhea events, 9,000 hospitalizations, 20,849 ED visits, 2,812 nosocomial infections and 6 deaths over 5 years.  The base case results show that a UMV program with RotarixTM could reduce these events by 69%, 81%, 68%, 76% and 79% respectively over 5 years. At $60 per dose plus $9 administrative fee, the cost per QALY gained over no vaccination is $28,653. CONCLUSIONS: A UMV program with RotarixTM is projected to substantially reduce the health and economic burden of rotavirus infections, and is cost-effective relative to no vaccination in the Canadian health care system.