Acute otitis media (AOM) is the most common pediatric bacterial infection, and stringently defined otitis-prone (sOP) children have immunologic deficiencies. We recently found that nasopharyngeal (NP) colonization by Streptococcus pneumoniae (Spn) elicits a NP mucosal antibody response to vaccine candidate pneumococcal proteins that correlate with protection from AOM in non-sOP (NOP) children. Here, we sought to determine if sOP children experience significantly higher colonization rates with Spn than NOP children, develop lower naturally acquired NP mucosal antibody responses to those same pneumococcal proteins after colonization by Spn, and suffer greater frequency of AOM as a consequence.