One of the major outer membrane proteins of nontypeable Haemophilus influenzae, P6, is highly conserved among strains, serves as a target for bactericidal antibody, and has been proposed as a possible vaccine candidate. The serum antibody response to P6 was studied in otitis-prone and normal children by an enzyme-linked immunosorbent assay. Of 20 otitis-prone children, 12 (60%) had a serum IgG antibody response to P6 after otitis media; however, the mean acute antibody level for the group, 4.6 micrograms/ml, was not significantly different from the convalescent level, 5.4 micrograms/ml. Anti-P6 antibody levels were also measured longitudinally for 10 to 25 months in 30 otitis-prone and 13 healthy children. Antibody levels increased sevenfold in the normal group compared with less than three-fold for the otitis-prone group and were significantly higher in the normal children after the age of 18 months (p < 0.05). Finally, otitis-prone children who had two or more episodes of otitis media with nontypeable H. influenzae did not have an anamnestic antibody response to P6. The failure to recognize P6 as a specific immunogen may account for recurrent infections. Moreover, the data suggest that otitis-prone children may not respond adequately to a vaccine containing P6.