Policy-makers require information on the potential benefits of and economic case for pneumococcal conjugate vaccination in middle-income countries. We built decision analysis models to evaluate a three-dose infant series of the 7-, 10- or 13-valent pneumococcal conjugate vaccines in 77 middle-income countries compared with no vaccination, accounting for direct protection of vaccinated children as well as herd protection and serotype replacement in unvaccinated children and adults. Over 10 years, pneumococcal vaccination would prevent at least 11.0 million cases and 314 000 deaths in children under-5, one-third of the pneumonia and invasive disease cases and deaths that would occur in this age group without vaccination. Herd protection would prevent 3.1 million cases and 163 000 deaths in older children and adults. A total of 11.1 million discounted disability-adjusted life-years (DALY) would be averted. At a dose cost of $10 for lower- middle-income and $20 for upper-middle-income countries, the net pooled (for all countries together) discounted vaccination cost would be $18.1 billion ($1600 per DALY averted). Vaccination would be cost effective for 72 countries with the 7-valent vaccine and for all countries with the 10- or 13-valent vaccines. The economic case for vaccination is compelling for middle-income countries.