OBJECTIVES: Herpes Zoster (HZ) and its most common complication, Post-Herpetic Neuralgia (PHN), are painful and debilitating conditions with an important burden for patients and society. A live-attenuated one-dose vaccine was licensed in 2006 for the prevention of both HZ and PHN in adults 50+ years old and is currently recommended and part of vaccination calendars in several countries. The objective of this study was to assess the cost-effectiveness of zoster vaccination for the 50+ population in Portugal. METHODS: An existing European Markov cohort model was adapted to the Portuguese healthcare setting. Health states considered are healthy, HZ, PHN, healthy post-HZ and death. HZ and PHN states are further split by pain severity (mild, moderate or severe). According to local guidelines, the cost-effectiveness outcomes were assessed from the societal perspective for a public reimbursement at 37%. Analysis comparing a HZ vaccination for adults aged ≥50 years with no vaccination was done. Input data were obtained from Portuguese sources whenever available. RESULTS: The strategy of vaccinating adults 50+ years old showed an incremental cost-effectiveness ratio of 19.625€ per quality adjusted life year (QALY) gained from a societal perspective. The analysis showed cost-effectiveness improvement with age with an ICER in the 65+ population of 15.517€/QALY from the societal perspective. The probabilistic sensitivity analyses showed that for high levels of certainty (95%) the ICER does not exceed 25.000€/QALY from the societal perspective. CONCLUSIONS: Considering the generally acceptable threshold, the present cost-effectiveness analysis demonstrates that HZ vaccination for adults 50+ years old in Portugal is a cost-effective strategy. Vaccine reimbursement would provide substantial health, social and economic benefits in the Portuguese health care context.