This study was undertaken to investigate and quantify the morphologic changes in the middle ear mucosa and connective tissue after the inoculation of graded doses (0.001 to 100 micrograms) of endotoxin prepared from Hemophilus influenzae. Histopathologic changes were observed in the middle ear mucosa in all animals. Marked bleeding and new bone formation in the submucosa were prominent at days 4 through 14. These findings indicate that the endotoxin from nontypable H influenzae is capable of inducing inflammation or pathologic changes in the middle ear mucosa and may play an important role in the pathogenesis of otitis media with effusion and its sequelae.