BACKGROUND Recurrent otitis media and acute otitis media treatment failure are commonly encountered in the pediatric population. OBJECTIVE To compare the clinical efficacy of gatifloxacin with amoxicillin/clavulanate for the treatment of acute otitis media treatment failure and recurrent otitis media. METHODS Three hundred fifty-four children 6 months-7 years with recurrent otitis media and/or acute otitis media failure were stratified according to age (younger than 2 years versus 2 years or older) and then randomly assigned to 10 days of treatment with gatifloxacin 10 mg/kg once daily or amoxicillin/clavulanate 90 mg/6.4 mg in 2 divided doses. Tympanocentesis was performed in 116 children with acute otitis media treatment failure and 52 with recurrent otitis media at study entry to validate the clinical diagnosis and provide microbiologic data. The primary outcome measure was clinical resolution of infection at the test-of-cure visit 3-10 days after completing treatment. RESULTS Clinical resolution of acute otitis media was observed in 79.0% (49 of 62) of clinically evaluable children younger than 2 years and 90.3% (56 of 62) of those 2 years or older who were treated with gatifloxacin as compared with 77.6% (45 of 58) of children younger than 2 years and 79.7% (47 of 59) of children 2 years or older treated with amoxicillin/clavulanate. In patients with acute otitis media treatment failure, clinical response rates for children younger than 2 years and those 2 years or older were 87.5% (21 of 24) and 97.0% (32 of 33) with gatifloxacin versus 63.6% (14 of 22) and 83.9% (26 of 31) with amoxicillin/clavulanate. The corresponding clinical response rates in patients with recurrent otitis media were 79.2% (19 of 24) and 85.7% (18 of 21) with gatifloxacin and 90.5% (19 of 21) and 76.0% (19 of 25) with amoxicillin/clavulanate. Clinical success in those subjects having pretreatment middle ear fluid pathogens was similar for the 2 regimens [80.0% (24 of 30) gatifloxacin, 77.1% (27 of 35) amoxicillin/clavulanate]. Emergence of fluoroquinolone-resistant strains was not observed. Both drugs were generally well-tolerated. Diarrhea was the most common drug-related adverse event (10% gatifloxacin, 18% amoxicillin/clavulanate). No evidence of abnormal joint or gait findings was found during a 12-month follow-up. CONCLUSIONS Gatifloxacin once daily is at least as effective and well-tolerated as amoxicillin/clavulanate twice daily in children with acute otitis media treatment failure or recurrent otitis media. There was no evidence of arthrotoxicity or emergence of fluoroquinolone-resistant bacteria in gatifloxacin-treated children.