The efficacy of concurrent treatment of experimental acute otitis media with ibuprofen and ampicillin was evaluated in chinchillas with respect to clearance of the effusion and resolution of mucosal inflammation. Sixty-four chinchillas were infected with Streptococcus pneumoniae and randomly assigned to treatment with either IM ampicillin (control) or ampicillin plus ibuprofen (experimental) beginning on day 2 post inoculation. On days 3, 6, 9 and 12, 8 animals from each group were killed, effusions recovered for biochemical assay and the right middle ears prepared for histological study. Between group differences in the number of ears with effusion and effusion volume were not statistically significant. Mucosal thickness and the frequencies of ears with histopathological signs of inflammation were significantly less in the experimental group when compared to the control group. Differences in the effusion concentrations of total protease, 3 of 4 hydrolytic enzymes and free fatty acids favoring the experimental group were observed at the 6, 9 and 12 day endpoints. Also, at those times the levels of the 3 measured products of the cyclooxygenase pathway were less in the experimental group. These results suggest that the addition of ibuprofen to ampicillin for the treatment of acute otitis media decreases production of select eicosonoids, reduces mucosal inflammation and alters the course of the disease in this model of bacterial infection.