A double-blind randomized clinical trial was conducted comparing cefaclor and amoxicillin for the treatment of acute otitis media with effusion in 110 children (150 ears). Each child underwent unilateral or bilateral tympanocentesis and then randomly received a 14-day course of either amoxicillin or cefaclor. Of 57 children in the cefaclor group, only 3 children (5.3%) had persistent or recurrent symptoms during the 14-day course of treatment, as compared to 5 of 53 children (9.4%) in the amoxicillin group, but this difference is not significant. After completion of the 14 days of therapy, 45 of 76 ears (59.2%) of the children in the cefaclor group were effusion-free, as compared to only 28 of 64 ears (43.7%) of the children in the amoxicillin group. When adjusted for age and race, this difference is statistically significant (p = .03). However, the difference between the effect of the two antimicrobials is not statistically significant in children. Cefaclor is a reasonable choice for antimicrobial therapy for acute otitis media with effusion, and from these study findings, it appears that cefaclor may be more effective than amoxicillin in resolving the middle ear effusion at the completion of 14-day therapy.