Rationale: The acute phase reactant and protease inhibitor 1-antichymotrypsin is considered to play a protective role in the airways, but it is not known. Objectives: We analyzed whether the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis interact with antichymotrypsin. Methods: We compared a series of clinical isolates in addition to wild type and ubiquitous surface protein-deficient Moraxella to study the nature of antichymotrypsin binding by the bacteria. Measurements and Main Results: M. catarrhalis was the only species that bound antichymotrypsin among 25 bacterial species tested by flow cytometry and a direct binding assay. Experiments with Moraxella mutants revealed that ubiquitous surface proteins A1 and A2 were responsible for the interaction, and using recombinant fragments, a consensus sequence within ubiquitous surface proteins A1 and A2 was defined. Binding of iodine labeled antichymotrypsin was dose dependent and strong (dissociation constant; Kd 24.9 - 44.8 nM). Moreover, a chymotrypsin activity assay showed that antichymotrypsin when bound to the bacterial surface was neutralized. Conclusions: Moraxella antichymotrypsin neutralization is a novel microbial virulence mechanism that may induce excessive inflammation resulting in more exposed extracellular matrix that is beneficial for bacterial colonization.