Pneumococcal surface protein A (PspA) is an important virulence factor of Streptococcus pneumoniae. PspA exists as two major families, which include variable but serologically cross-reactive proteins. Previous studies with a family 1 PspA antigen suggested that children develop low concentrations of anti-PspA after pneumococcal carriage or infection. In this study, antibody to PspA families 1 and 2 was measured by an enzyme immunoassay of the serum and saliva of children with a history of culture-proven pneumococcal colonization and/or acute otitis media and in the serum and saliva of adults. The PspA families of the pneumococcal strains isolated from children were determined. The majority of the children had high serum and salivary anti-PspA concentrations to the PspA family they had encountered and low concentrations to the other, whereas adults had high antibody concentrations to both PspA families, both in serum and in saliva. The results suggest that children have a relatively family-specific antibody response to the PspA family they have been exposed to and that any PspA vaccine for children should contain members of both major PspA families. Copyright © 2008, American Society for Microbiology. All Rights Reserved.