Nontypeable Haemophilus influenzae (NTHi) is a Gram negative, non-capsulated coccobacillus commensal of the nasopharyngeal tract. Acting as an opportunistic pathogen is responsible for different pathologies such as exacerbation of COPD, Otitis Media and in worst cases meningitis and sepsis. Given the great genetic variability among NTHi strains, the greatest challenge in the formulation of a vaccine against NTHi is the identification of cross protective antigens. Under the Novartis legacy (now GSK), several antigens were identified thanks to a reverse vaccinology and proteomic approaches. The ability of antibodies raised against those antigens to induce complement-mediated killing was tested in Serum Bactericidal Assay against a large panel of NTHi clinical strains; interestingly 20% of tested strains results to be resistant. Moreover these strains were also capable to evade the complement-mediated killing induced by normal human serum itself. We determined the cause of NTHi serum resistance as the ability to avoid C3 deposition on the bacterial surface, escaping the complement classical and lectin pathways activation. Like other bacterial pathogens NTHi is able to evade the C3 deposition seizing C4BP from the bloodstream. We assessed the ability of the resistant strains to bind C4BP, in comparison to sensitive strains, performing serum resistance assay, flow cytometry analysis and confocal microscopy. From literature it is known that binding of C4BP can be dependent on the decoration of the LOS. Therefore, a correlation between the Phosphorylcholyne (ChoP) expression and C4BP binding was investigated. We identified by Western blot and flow cytometry assay a negative correlation between ChoP expression and C4BP binding. Only sensitive strains resulted to decorate the LOS with ChoP. The essential role of C4BP in determining NTHi serum resistance was further confirmed depleting C4BP from the human serum. In absence of C4BP resistant strains became sensitive to killing. Finally, through a combined approach of co-immunoprecipitation technique and mass spectrometry, we identified Outer Membrane Protein P2 (Omp P2) as the putative protein responsible for the C4BP binding. Being Omp P2 a ubiquitous porin protein, well documented in literature, with highly conserved and highly variable extracellular domains, structural differences in this protein could be responsible for the different ability of the strains to bind C4BP determining then different susceptibility.