OBJECTIVES: This study aims to examine vaccine effectiveness (VE) estimates used in cost-effectiveness studies that compared the 23-valent pneumococcal polysaccharide vaccine (PPSV23) to the 13-valent pneumococcal conjugate vaccine (PCV13) for adults, and assess how differences in VE estimates affect the estimated incremental cost-effectiveness ratios (ICER). METHODS: A targeted literature review was performed to identify cost-effectiveness analyses of PPSV23 vs. PCV13 in adults. A comparative assessment of input parameter values used in these analyses was performed and their relationship to model results was examined. RESULTS: Four models that evaluated the cost-effectiveness of PPSV23 vs. PCV13 in adults were identified. All models estimated that PPSV23 protected against more vaccine-type infections than PCV13. However, each model assumed different VE estimates in preventing invasive pneumococcal disease (IPD) and non-bacteremic pneumococcal pneumonia (NBPP). PCV13 VE estimates for adults were derived from pediatric clinical efficacy data either directly or via Delphi panels. PPSV23 VE estimates were obtained from meta-analyses of randomized trials or observational studies in adults either directly or with Delphi panels. For vaccine-type IPD, base-case VE estimates were relatively consistent among the studies for immunocompetent adults (PPSV23: 57%-93%; PCV13: 61%-94%) but varied for immunocompromised adults (PPSV23: 0%-18%; PCV13: 48%-71%). For vaccine-type NBPP, VE estimates varied for immunocompetent adults (PPSV23: 0%-60%; PCV13: 50%-74%) and immunocompromised adults (PPSV23: 0%, PCV13: 6%-35%). Model results showed that PCV13 had lower ICERs than PPSV23 when PPSV23 efficacy for NBPP was assumed to be 0%, while PPSV23 had lower ICERs than PCV13 when PPSV23 was assumed effective in preventing NBPP in immunocompetent adults. CONCLUSIONS: Cost-effectiveness results for adult pneumococcal vaccination were highly sensitive to VE estimates. With the absence of head-to-head clinical efficacy data comparing PPSV23 to PCV13 and the influence these data have on model results, sensitivity analyses are needed when considering potential policy implications of these cost-effectiveness studies.