OBJECTIVES: To predict the cost-effectiveness of vaccination with measles, mumps, rubella, and varicella (MMRV) vs MMR in Mexico. METHODS: A dynamic mathematical model was used to reproduce the age-related incidence of varicella and zoster. The impact of introducing varicella vaccination was predicted at population-level including costs and quality of life. Empirical age-specific contact rates between individuals were used. Vaccine efficacy against varicella was assumed to be 95% after two doses (1y and 6y). We assessed the impact of vaccination in a base-case (coverage dose1: 90%; dose2: 80%) and in an optimal scenario (higher coverage dose1:95%; dose2:90% and catch-up programme); and the cost-effectiveness of replacing MMR with MMRV using 1.5% and 3% discount rates for benefits and costs.                                                                                                                                                   RESULTS: In the long-term, MMRV vaccination is predicted to result in a ~90% decrease in varicella incidence (with short-term epidemics due to rebound effect) and a ~90% decrease in zoster cases (with a temporary increase due to the assumption on exogenous boosting). At 1, 5, 30, and 80 years, MMRV vs MMR is predicted to result in: -          more QALYs saved (31, 209, 925, and 1306); -          more complications avoided (2, 6, 132, 1864); and -          less deaths in the long-term (though more in the short-term) (0, -5, -105, 279). Despite increased vaccine costs vs MMR, MMRV was cost saving at all time points in terms of GP/outpatient, hospital, indirect, and total ($7.9, $56.5, $226.9, and $331.2 million, respectively) costs. Cost-effectiveness planes for direct and total costs indicate that MMRV would provide more QALYs than MMR, and is cost saving. These results are for the base-case scenario. For optimal scenario, results were similar or even better. CONCLUSIONS: MMRV vaccination should result in significant reduction in varicella and zoster cases in the long-term. We predict the replacement of MMR by MMRV to be dominant under both scenarios.