Policy-makers increasingly rely on cost-effectiveness analysis, in addition to clinical effectiveness, when considering the introduction of new childhood vaccines. A previous analysis determined vaccination of infants with 7-valent pneumococcal conjugate vaccine (PCV) to be highly cost effective in preventing child mortality in countries eligible for financial support from the Global Alliance for Vaccines and Immunization (GAVI). We aimed to update this analysis by incorporating recent data on global disease burden, indirect effects and higher valency vaccines. Decision analytic models were built using an incidence-based approach in order to evaluate a three-dose vaccination schedule of infants in 72 GAVI-eligible countries over a 10-year programme. Seven-, 10- and 13-valent vaccine formulations were each compared with no vaccination. Depending on the formulation used, PCV could avert 294 000–603 000 deaths and 9.3–17.6 million disability-adjusted life-years (DALY) annually. The majority (91%) of the DALYs averted would be through the vaccine's direct effects in children under-5. Using WHO thresholds and a negotiated average dose cost, PCV would be highly cost effective in 69 of 72 GAVI-eligible countries. This finding was robust when assumptions regarding disease epidemiology and vaccine-related effects were varied in sensitivity analyses. The current analysis supports PCV introduction in GAVI-eligible countries owing to its potential to avert substantial numbers of deaths at relatively low incremental costs.