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One-dose universal varicella vaccination (UVV) was introduced in the Argentinian National Immunization Program in July 2015. This study examined the impact of one-dose UVV on varicella incidence and mortality in Argentina. Incidence and mortality data were obtained from official databases for pre-UVV (January 2008–June 2015) and post-UVV (July 2015–December 2019) periods. Time series analyses with autoregressive integrated moving average (ARIMA) modeling predicted varicella incidence and mortality in absence of UVV in the target (aged 1–4 years) and overall population. Predicted and observed values post-UVV were compared to estimate UVV impact. Mean annual incidence rates per 100,000 reduced from 1999 (pre-UVV) to 1122 (post-UVV) in the target population and from 178 to 154 in the overall population. Significant declines in incidence were observed, reaching reductions of 83.9% (95% prediction interval [PI]: 58.9, 90.0) and 69.1% (95% PI: 23.6, 80.7) in the target and overall populations, respectively, during peak months (September-November) post-UVV. Decreasing trends in mortality rate from 0.4 to 0.2 per 1,000,000 population were observed. Over the last four years, one-dose UVV has significantly reduced varicella burden of disease in Argentina. Continuous efforts to improve vaccination coverage rates and long-term follow-up are needed to better understand the benefits of the UVV program.