Unlike the elderly, healthy middle aged adults are at relatively low risk of acquiring serious pneumococcal disease. An explanation that has been proposed is that people in this age group have significant amounts of serum antibody (primarily IgG2) that react with any pneumococcal capsular polysaccharide serotypes. The level of antibody can be as high as several hundred micrograms per milliliter of blood for some serotypes. A significant component of this reactivity is directed toward the conserved C-polysaccharide depletion. Even after C-polysaccharide depletion, which is included as a routine part of the assay to determine antibody levels, resting antibody levels in a normal healthy adult population can vary widely. We have analyzed the reactivity of serum from 76 people to 16 pneumococcal capsular polysaccharide serotypes. The antibody reactivities to 13 of 16 serotypes are highly correlated with one another. Depletion of serum with C-polysaccharide and purified capsular polysaccharide inhibited antibody binding to type specific capsular polysaccharide. Cross-serotype inhibition of antibody binding was also observed. This indicates that there are materials contained within the pneumococcal polysaccharides that contribute to the cross-reactivity of serum antibodies in people that have not been vaccinated with the pneumococcal vaccine.