The safety and efficacy of clarithromycin was compared with those of amoxicillin-potassium calvulanate for the treatment of acute otitis media in children. In a multicenter, randomized, investigator-blinded trial, 180 patients (6 months to 12 years of age) with acute otitis media were allocated to receive either clarithromycin, 15 mg/kg in two divided doses (n = 90), or amoxicillin-clavulanate, 40 mg/kg in three divided doses (n = 90), for 10 days. Middle ear samples were obtained by tympanocentesis from 175 of 180 patients. Pathogens were isolated from 137 samples (76%). Eighty-six patients in each treatment group were considered for efficacy analysis. Clinical cure or improvement was achieved within 4 days after treatment in 80 (93%) of 86 patients receiving clarithromycin and in 82 (95%) of 86 patients receiving amoxicillin-clavulanate. Recurrence of infection was observed between 5 and 35 days after treatment in 9 (11%) of 80 patients in the clarithromycin group and in 8 (10%) of 82 patients in the amoxicillin-clavulanate group. Middle ear effusion was found with similar frequency at the end of therapy and at follow-up visits in both treatment groups. Mild gastrointestinal signs and symptoms, the most common side effects, were noted in 20% and 52% of patients in the clarithromycin group and the amoxicillin-clavulanate group, respectively (p < 0.001). We conclude that clarithromycin is a safe and effective antimicrobial agent for the treatment of acute otitis media in children.