This trial compared the efficacy and safety of a 10-day treatment course of cefaclor and cefuroxime axetil in the treatment of acute otitis media with effusion in children who failed therapy with amoxicillin. This was an investigator-blind, randomized, parallel treatment group study. To be included, patients must have received treatment with a standard clinical regimen of amoxicillin for at least 48 hours and not more than 10 days, with the last dose within 72 hours of randomization. Patients who met the entry criteria were randomly assigned to one of two antibiotic treatment groups. Cefaclor and cefuroxime axetil suspensions were administered twice daily for a total daily dose of 40 mg/kg and 30 mg/kg, respectively. Physical examination, pneumatic otoscopy and tympanogram were performed to evaluate efficacy to therapy. Therapeutic equivalence was established by ruling out a difference (cefaclor minus cefuroxime axetil) of 15% in percentages of clinical success (cure plus improvement). Safety evaluation was performed by assessment of clinical adverse events. In the intent-to-treat analysis post-therapy (1-6 days after completion of therapy), 96 of 104 (92.3%) cefaclor-treated patients had clinical success compared to 90 of 101 (89.1%) cefuroxime axetil patients. The 95% confidence limits on the difference between proportions of favorable outcomes (cefaclor minus cefuroxime axetil) was from -4.8% to +11.2%. At termination of the study (day 10-16 after completion of therapy), 86 of 104 (82.7%) cefaclor patients and 84 of 101 (83.2%) cefuroxime axetil patients had favorable clinical outcomes (95% confidence interval: -10.8% to +9.9%). Thirty-two (30.8%) of the 104 patients in the cefaclor treatment group reported at least one adverse event, with rhinitis reported in 9 (8.7%) patients and cough increased in 7 (6.7%) patients. Thirty-six (35.6%) of the 101 patients in the cefuroxime axetil treatment group reported at least one event, with diarrhea reported in 11 (10.9%) of patients and rhinitis in 10 (9.9%) patients. Cefaclor and cefuroxime axetil were equally effective in the treatment of patients with acute otitis media with effusion who had failed therapy with amoxicillin. Significantly fewer patients treated with cefaclor reported diarrhea, which is the most frequently reported adverse event in children treated with antibiotics for this disease.