Acute otitis media (AOM) is the most common reason for outpatient antimicrobial therapy today. With increasing problems with antibiotic resistance, a more restrictive use of antibiotics has been advocated for both single and recurrent episodes. The arguments advanced have been immunological as well as ecological. To study the effects of a 5 day course of amoxicillin on recurrent AOM caused by non-typeable Haemophilus influenzae, Sprague-Dawley rats were used. Amoxicillin was introduced at the clinical peak of the first infection. One month later the animals were rechallenged. Local and systemic changes were monitored by otomicroscopy, bacterial cultures, and analyses of systemic IgG responses and histological changes. Antibiotic treatment accelerated the resolution of the primary infection. After resolution, only minor morphological changes were observed. The protective rate at rechallenge was 100% in the treatment group, compared with 80% in the untreated control group. Although the production of serum IgG antibodies was initially slightly impeded by the treatment, it was significantly higher in treated animals after rechallenge. Major structural changes could not be avoided at the second infection, however, and a significantly higher frequency of myringosclerosis was observed in treated animals. These experimental findings constitute support for further studies of antimicrobial drugs and recurrent AOM.