Non-typeable Haemophilus influenzae (NTHi) is the most common bacteria responsible for episodic acute otitis media (AOM; non-otitis prone), recurrent AOM (rAOM; otitis prone) and AOM treatment failure (AOMTF) in children. In this 3.5 years of prospective study, we measured the serum antibody response to outer membrane proteins D, P6 and OMP26 of NTHi in children with AOM (n=26), rAOM (n=32), AOMTF (n=27). The geometric mean titers (GMTs) of IgG at their acute AOM visit against Protein D in otitis prone children were significantly lower compared to AOMTF (p value<0.01) and non-otitis prone (p value<0.03) children; otitis prone children had significantly lower IgG levels to P6 compared to AOMTF children (p value<0.02); otitis prone children had significantly lower IgG levels to OMP26 compared to AOMTF children (p value<0.04). Comparing acute to convalescent titers after AOM, otitis prone and AOMTF children had no significant change in total IgG against all the three proteins, while non-otitis prone children had significant increases to Protein D. Anti-protein D, P6 and OMP26 antibody levels measured longitudinally during NP colonization between age 6 and 24 months in 10 otitis prone children and 150 non-otitis prone children showed <2-fold increases over time in otitis prone children compared to >4 fold increases in the non-otitis prone children (p value<0.001). We conclude that otitis prone children mount less of an IgG serum antibody response toward Protein D, P6 and OMP26 after AOM which may account for recurrent infections. The data on acute sera of otitis prone vs non-otitis prone children and the acute-to-convalescence response in non-otitis prone children point to a possible link of anti-PD to protection. Moreover, the data suggest that otitis prone children should be evaluated for their responses to Protein D, P6 and OMP26 vaccine antigens of NTHi.