Abstract: Background A new adjuvanted subunit vaccine (HZ/su), with higher vaccine efficacy than live-attenuated vaccine (ZVL), has been licensed in Europe since March 2018. Therefore, Belgian decision-makers might need to re-assess their recommendations for vaccination against herpes zoster (HZ). Methods We conducted a cost-effectiveness analysis, using a Markov decision tree, of vaccinating 50- to 85-year-old immunocompetent Belgian cohorts with no vaccination, HZ/su, ZVL, and ZVL with booster after 10 years. Due to the uncertainty in vaccine waning of HZ/su vaccine beyond 4 years, we used a logarithmic and 1-minus-exponential function to model respectively a long and short duration of protection. We used a lifetime time horizon and implemented the health care payer perspective throughout the analysis. Results HZ/su had the greatest impact in avoiding health and economic burden. However, it would never become cost-effective at a willingness-to-pay threshold of euro40,000 per quality-adjusted life year (QALY) gained at its market price set by the manufacturer in the USA. Depending on the waning function assumed for HZ/su, the price per dose needs to drop 60% or 83% such that vaccination with HZ/su, assuming respectively a long or short duration of protection, would become cost-effective in 50- and 80-year-old individuals. At euro40,000 per QALY gained, ZVL or ZVL with booster was never found cost-effective compared with HZ/su, even if only administration cost was considered. Conclusion HZ/su is cost-effective in the 50-year-old age cohort at the unofficial Belgian threshold of euro40,000 per QALY gained, if its price drops to euro55.40 per dose. This result is, however, very sensitive to the assumed duration of protection of the vaccine, and the assumed severity and QALY loss associated with HZ and post-herpetic neuralgia (PHN).