BACKGROUND: Immune function declines with age and has been associated with reduced vaccine responsiveness. Chronic infection with cytomegalovirus (CMV) has been proposed as a contributor to poorer responses in older adults. A pneumococcal vaccine has been recommended in the United Kingdom for those aged >65 years since 2003 to prevent pneumococcal disease. METHODS: We evaluated the effect of age and CMV status on pneumococcal vaccine responses in 348 individuals aged 50-70 years. RESULTS: We found participant age to be associated with serotype-specific and functional antibody titers after pneumococcal vaccination, with a mean 6.2% (95% confidence interval, 2.9%-9.5%) reduction in postvaccination functional antibody titers per year. CMV status was not associated with serotype-specific immunoglobulin G concentrations or functional antibody titers after pneumococcal vaccination. However, CMV seropositivity was associated with higher levels of prevaccination functional antibody for 4 of 7 pneumococcal serotypes assessed. CONCLUSIONS: These data imply that CMV infection is not directly responsible for the decline in pneumococcal vaccine responses seen with age but suggest that CMV-seropositive individuals differ in their natural exposure to pneumococci or have altered mucosal immune responses after colonization with this organism.