Penicillin V (pcV) was administered to 50 rats, either before bacterial challenge (prevention group), or after bacterial challenge but before fulminant purulent acute otitis media (AOM) was established (early treatment group). Five animals from each group were killed on days 4, 8, and 12, and 2 and 6 months after challenge. Middle ear mucosa was sampled at six different sites and studied in the light microscope. Untreated pneumococcal AOM in the rat has been shown to cause persistent structural changes of the middle ear mucosa. Both in the early treatment group and in the prevention group, the structural changes were diminished, as compared with those of untreated infected controls. The persistent structural changes seen after 6 months in untreated controls were not seen in animals that had received pcV in conjunction with the AOM episode. Though the beneficial effect on the mucosal changes during the first 2 weeks was more pronounced when pcV was given prophylactically, its use as early treatment would seem to be almost as effective in preventing the persistence of mucosal changes.