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Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative human pathogen that causes infections mainly in the upper and lower respiratory tract. The bacterium is associated with bronchitis and exacerbations in patients suffering from chronic obstructive pulmonary disease and frequently causes acute otitis media in preschool children. We have previously demonstrated that the binding of C4b binding protein (C4BP) is important for NTHi complement evasion. In this study, we identified outer membrane protein 5 (P5) of NTHi as a novel ligand of C4BP. Importantly, we observed significantly lower C4BP binding and decreased serum resistance in P5-deficient NTHi mutants. Surface expression of recombinant P5 on Escherichia coli conferred C4BP binding and consequently increased serum resistance. Moreover, P5 expression was positively correlated with C4BP binding in a series of clinical isolates. We revealed higher levels of P5 surface expression and consequently more C4BP binding in isolates from the lower respiratory tract of chronic obstructive pulmonary disease patients and tonsil specimens compared with isolates from the upper respiratory tract and the bloodstream (invasive strains). Our results highlight P5 as an important protein for protecting NTHi against complement-mediated killing., This work was supported by the Swedish Heart Lung Foundation (20180401), the Swedish Research Council (2019-01053 to K.R.; 2018-02392 to A.M.B.), the Anna och Edwin Berger foundation (to K.R.), the Torsten Söderberg Foundation (to A.M.B.), the Royal Physiographical Society in Lund Hedda and John Forssman Foundation (to O.T. and S.B.), the O. E. och Edla Johanssons Foundation (to S.B.), the Längmanska Kulturfonden (to S.B.), the Tore Nilsson’s Foundation (to S.B.), and Skåne County Council’s Research and Development Foundation (to K.R. and A.M.B.).