The middle ear cleft is a modified gas pocket which functions normally when the gas contents are regulated by a normal eustachian tube, resulting in equalization of middle ear pressure to that of the environment. The most important regulator of this middle ear pressure is the eustachian tube, a critical passageway from the nasopharynx into the middle ear. Any alteration of eustachian tube mucociliary function caused by virus, allergy, pollutants, or alteration of the normal homeostasis of the nasopharynx will result in eustachian tube obstruction. This, in turn, leads to underventilation of the middle ear, and transudation of fluid. If bacteria or virus or viral-bacterial interaction leads to infectious disease of the middle ear, an immune response is produced as a result of the inflammatory response, allowing lymphocytes and antigen-presenting cells to enter into the middle-ear mucosa. This article summarizes the immunologic reactivity in the middle ear following a viral-bacterial inflammatory reaction in the middle-ear mucosa. Although secretory IgA is critical for protection of the nasopharynx, its function in the middle ear has still not been resolved. The evidence strongly suggests that IgG1 and IgG3 subclasses are responsible for eradication of middle ear pathogens. Finally, a review of alternative approaches to the prevention of otitis media is briefly discussed in this critical period of emergence of resistant bacteria to available antibiotics.