Expert panels have recommended high-dose amoxicillin (80-90 mg/kg/day) as the therapy of choice for uncomplicated acute otitis media in children. This recommendation is based primarily on pharmacokinetic data predicting bacteriologic cure of most middle ear infections by using amoxicillin at the recommended dosage. However, comparisons of aminopenicillin-containing regimens with alternative treatments, particularly azithromycin, have not consistently demonstrated superiority of the former, even in recent trials with stringent designs. Moreover, amoxicillin exposure may perturb nasopharyngeal colonization more profoundly than do alternative agents. These perturbations may theoretically promote the dissemination of beta-lactam-resistant pneumococci in the community more than other drugs approved for use in otitis media. Such findings suggest that several factors should be considered when choosing an agent to treat otitis media and that reexamination of high-dose amoxicillin as the superior first-line agent for this condition might be warranted.