Each of the anatomic structures of the ear (external, middle, and inner) is subject to immunologic influence and injury. Studies in experimental animals have shown that primary immune responses to foreign antigens can be induced within the middle and inner ear as indicated by (1) infiltration and local persistence of mononuclear leukocytes and plasma cells, (2) appearance of antibody in perilymph, and (3) eventual development of systemic immunity. Protective effects of inner ear immunization against subsequent viral challenge have also been shown. Clinically, otologic disease can occur in association with a wide variety of systemic autoimmune and immunologic disorders: systemic lupus erythematosus, rheumatoid arthritis, Behçet's disease, Sjögren's syndrome, relapsing polychondritis, ulcerative colitis, Cogan's syndrome, and vasculitis-related disease. Evidence for immunologic involvement has also been found in cases of idiopathic sensorineural hearing loss frequently accompanied by vestibular-dysfunction (Meniere's disease). Many of these cases progress into systemic autoimmune disorders. Autoimmune-associated hearing loss has been recognized as one of the few types of treatable hearing dysfunction, with good responses to immunosuppressive therapy. The pathogenesis of autoimmune-related otologic disease has not been established; however, evidence suggests three possible types of immunologic injury: (1) autoantibody binding to type II collagen or other otologic components (type II immunologic injury); (2) immune complex formation leading to vasculitis (type III); and (3) T cell-mediated autoreactivity to inner ear membranous elements (type IV). These mechanisms may not be mutually exclusive. Clinical laboratory procedures should be directed at evaluating these possibilities to assist in diagnosis.