Despite the high incidence and prevalence of otitis media, its pathogenesis is not thoroughly understood. In the last decade, many efforts have been made to provide a better understanding, and abundant information has become available. At the same time the field of immunology has advanced at an extremely rapid pace. We have followed the gradual cellular events in the defense reaction of the middle ear, utilizing eustachian tube obstruction to induce otitis. Seventy-five cats were divided in groups and sacrificed at intervals between one day and six months, and their temporal bones were studied. During an initial phase of inflammation, polymorphonuclears appear at three days in connective tissue; at the same time active fibroblasts synthesize tropocollagen and ground substance while epithelial cells secrete mucus and lysozymes. These cells, together with those involved in the mucociliary transport system and a patent functional eustachian tube, constitute the nonspecific system of defense. The transition cells are the macrophages which appear at one week to interact with T and B cells to produce the specific immune response. Plasma cells appear at two weeks to peak at one month with synthesis of immunoglobulins A, G and M. A secretory immune system is observed. At three and six months, lymphocytes are the predominant cells and occasional accumulations of mononuclears are observed. The reaction involves the entire middle ear, including mucoperiosteum, middle ear muscles and round window membrane. We believe that a better understanding of the middle ear defense system will lead in time to a practical clinical assessment of the immunological status during the evolution of each particular process or disease involving the middle ear, and a more rational approach to the treatment and, hopefully, prevention of chronic ear disease.