Two vaccines, 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13), are widely available for the prevention of pneumococcal disease in adults. However, it is unclear how cost-effective these pneumococcal vaccine choices are in the Hong Kong healthcare environment. We aimed to assess the cost-effectiveness of a sequential administration of PCV13 followed by PPSV23 compared to a single dose of PPSV23 vaccination for pneumococcal disease control in Hong Kong adults aged ≥65 years and individuals aged 20-64 years with immunocompromising and chronic conditions. A previously developed deterministic cohort sequential model was applied to compare the outcomes of two vaccination strategies from a societal perspective. Population-specific model input, including incidence, mortality, case-fatality, risk group distribution, vaccination costs, disease management, and productivity loss, was estimated from a Hong Kong-wide electronic medical database. Costs were valued in US$ in 2017. Vaccination strategies with an incremental cost-effectiveness ratio (ICER, defined as incremental cost per QALY saved) less than one local GDP per capita ($46,193 in 2017) were defined as highly cost-effective. Deterministic sensitivity analyses (SA) were conducted. Compared with single-dose PPSV23, sequential vaccination of PCV13 followed by PPSV23 was cost-saving for adults aged ≥20 years. In the deterministic SA, the base-case results were robust for tested parameter uncertainties. Future vaccination policies should consider the cost-effectiveness of a sequential vaccination strategy as a measure to reduce the vaccine-preventable pneumococcal disease burden in Hong Kong.