The relationship between nasopharyngeal colonization with nontypeable H. influenzae and recurrent otitis media was assessed in 157 children followed prospectively from birth through 12 months of age. Forty-nine (31%) became colonized. Nasopharyngeal secretory IgA (sIgA) reactive with the P6 outer membrane protein was detected in all colonized children. Reduction or elimination of the organism was associated with a better mucosal immune response (560 +/- 864 units/ng/mL of sIgA) than was persistence in the nasopharynx (121 +/- 81; P = .04). Forty colonized children (82%) and 61 noncolonized children (56%) developed otitis media (P = .004); colonized children were four times more likely to be classified as otitis prone (P = .003). The frequency of otitis media episodes was directly related to the frequency of colonization (r = .42, P < .01). These results demonstrate a strong relationship between nasopharyngeal colonization patterns and otitis media. The mucosal immune response may be important in elimination of potential pathogens from the respiratory tract.