OBJECTIVE This trial compared the efficacy of ceftibuten with that of amoxicillin in resolving otitis media with effusion. METHODS Two hundred ten children with otitis media with effusion were randomly assigned to receive either ceftibuten (9 mg/kg/day in one daily dose) or amoxicillin (40 mg/kg/day divided into 3 daily doses) for 14 days. Outcome was assessed at 2 and 4 weeks in all subjects; those without middle ear effusion at the 4-week visit were examined at 8, 12 and 16 weeks. Middle ear status was determined by pneumatic otoscopy and by an algorithm combining pneumatic otoscopy with tympanometry. RESULTS The percentages of subjects who were effusion-free in the ceftibuten and amoxicillin groups at 2 weeks by otoscopy were 29.8 and 27.2%, respectively (P = 0.59), and by the algorithm, 23.4 and 20.4%, respectively (P = 0.47). In children who were effusion-free at 2 weeks, recurrence of effusion by 16 weeks was noted in approximately 60% of the ceftibuten group and 67% of the amoxicillin group. No medication side effects were reported by 88% of subjects in the ceftibuten group and by 93% of subjects in the amoxicillin group. We found no significant differences between the ceftibuten and amoxicillin groups with respect to resolution of middle ear effusion, rate of recurrence or side effects. CONCLUSIONS Amoxicillin remains the drug of first choice for treatment of otitis media with effusion when treatment is deemed advisable, but ceftibuten may be an alternative drug in selected situations.