For investigation of the nature and origin of middle ear effusions, immunochemical studies were performed on more than 400 patients diagnosed as having otitis media with effusion. Although results of cellulose acetate and disc electrophoretic analyses and quantitation of IgG, IgA, and IgM suggested that proteins found in the effusions were derived for the most part from the serum, quantitative analysis of secretory IgA revealed the existence of appreciable amounts of secretory IgA in both serous and mucoid effusions. The antigenicity and subunit structure of the secretory IgA isolated from middle ear effusions were identical or very similar to those of secretory IgA obtained from other external secretions. Radioactive single radial diffusion analysis of IgE showed that the mean concentrations of IgE in effusions and sera were within normal ranges. Findings of this study suggest that the middle ear maintains the local immunologic defense system, that the middle ear effusion is at least partially an external secretion, and that IgE in middle ear effusions obtained from old patients, rather than being a local product, may be derived from the serum.