The interference of antibodies to pneumococcal cell wall polysaccharide (CWPS) in the measurement of antibodies to capsular polysaccharides in children was assessed after vaccination with pneumococcal polysaccharide vaccine. ELISAs were developed to measure IgG subclasses specific for pneumococcal types 3, 6, 19, and 23 and CWPS. Analysis of antibody levels to all four capsular polysaccharides was affected by the presence of antibodies to CWPS, and their removal altered both anti-capsular polysaccharide antibody levels and the interpretation of responses to the vaccine. Thus, it is likely that CWPS contaminating pure capsular polysaccharide reagents used in most standard immunoassays is responsible for falsely elevated measurements of antibodies to capsular polysaccharide and the incorrect assessment of anti-pneumococcal antibody status in childhood.