Background <p>Varicella vaccination is not currently included in Portugal’s childhood national immunization program. We modeled the clinical and economic impact of a two-dose universal varicella vaccination (UVV) program in Portugal.</p> Methods <p>A dynamic transmission model was adapted to Portugal to assess the impact of UVV over a 50-year time horizon. Two two-dose UVV strategies (first dose at 12 months, second dose at 5 years) were compared to no vaccination. Clinical outcomes included varicella and herpes zoster incidence rates, cases, deaths, quality-adjusted life years (QALYs) lost, and varicella-related health care resource use. Costs were assessed from the payer perspective (direct costs of treatment) and societal perspective (direct costs plus indirect costs of lost workdays).</p> Results <p>Both UVV strategies reduced total varicella cases by 79.4–85.3%, outpatient visits by 78.9–84.8%, and varicella hospitalizations by 69.3–71.3% compared to no varicella vaccination. Herpes zoster cases were reduced by 2.4–2.9%. These strategies resulted in the gain of 5977–6094 QALYs and cost savings of €12.0 million (M)–15.9M from the payer perspective and €84.2M–93.9M from the societal perspective.</p> Conclusions <p>A two-dose UVV program is estimated to substantially reduce the burden of varicella disease in Portugal and to be cost-saving from both the payer and societal perspectives.</p>