Moraxella (Branhamella) catarrhalis is a common cause of otitis media in children and respiratory infection in adults with chronic obstructive pulmonary disease. To identify immune responses that may facilitate the development of a mucosal vaccine, a mouse model to study pulmonary responses was established. Regimes involving intra-Peyer's patch, intratracheal and intranasal routes of immunisation with killed M. catarrhalis were investigated. A mucosal immunisation regime of a primary intra-Peyer's patch immunisation with an intratracheal boost resulted in significantly enhanced pulmonary clearance of bacteria compared to controls following an intratracheal challenge with live bacteria. Additional intratracheal boosts did not induce further enhancement of clearance. Intra-Peyer's patch immunisation alone, intratracheal and intranasal immunisations did not induce enhanced clearance. The levels of specific IgG and IgA in serum and bronchoalveolar lavage fluid correlated with pulmonary clearance. The present study showed that mucosal immunisation induced enhanced pulmonary clearance of M. catarrhalis following live bacterial challenge. This mucosal immunisation model has demonstrated that a mucosal vaccine, particularly an oral vaccine, would be feasible.