OM, or inflammation of the middle ear, is a highly prevalent infection in children worldwide. OM is a multifactorial disease with multiple risk factors, including preceding or concurrent viral URT infection. Hence, OM is also a polymicrobial disease. The mechanisms by which viruses predispose to bacterial OM are replete; however, all are predicated on the general principle of compromise of primary host airway defenses. Thus, despite an as-yet incomplete understanding of the molecular mechanisms involved in bacterial superinfection of a virus-compromised respiratory tract, the URT viruses are known to induce histopathology of airway mucosal epithelium, up-regulate expression of eukaryotic receptors used for bacterial adherence, alter the biochemical and rheological properties of airway mucus, and affect innate and acquired host immune functions, among others. Although discussed here in the context of OM, during preceding or concurrent viral infection of the human respiratory tract, viral impairment of airway defenses and the resulting predisposition to subsequent bacterial coinfection are also known to be operational in the mid and lower airway as well.