Objectives: A randomized, double-blind, double-dummy, multicenter international study was conducted to assess the clinical and bacteriologic response, safety, and compliance of a single 60-mg/kg dose of azithromycin extended-release (ER) versus a 10-day regimen of amoxicillin/clavulanate 90/6.4 mg/kg per day in children with acute otitis media at high risk of persistent or recurrent middle ear infection. Methods: Children aged 3 to 48 months were enrolled and stratified into two age groups (≤24 months and >24 months). Pretreatment tympanocentesis was performed at all sites and was repeated during treatment at selected sites. Results: The primary endpoint, clinical response at the test-of-cure visit in the bacteriologic eligible population, was achieved in 80.5% of children in the azithromycin ER group and 84.5% of children in the amoxicillin/clavulanate group (difference – 3.9%; 95% confidence interval – 10.4, 2.6). Bacteriologic eradication was 82.6% in the azithromycin ER group and 92% in the amoxicillin/clavulanate group (p = 0.050). Children who received amoxicillin/clavulanate had significantly higher rates of dermatitis and diarrhea, a greater burden of adverse events, and a lower rate of compliance to study drug compared to those who received azithromycin ER. Conclusions: A single 60-mg/kg dose of azithromycin ER provides near equivalent effectiveness to a 10-day regimen of amoxicillin/clavulanate 90/6.4 mg/kg per day in the treatment of children with acute otitis media.