A double-blind randomized clinical trial was conducted at two sites comparing cefaclor and amoxicillin for the treatment of acute otitis media with effusion in 214 children (293 ears). Each child underwent unilateral or bilateral tympanocentesis and then was randomly assigned to receive a 14-day course of either amoxicillin or cefaclor. The symptomatic clinical response was the same for the two antibiotics, with four children considered "treatment failures" in each antibiotic treatment group. By 14 days after entry into the study 59 of 106 children (55.7%) in the cefaclor group had ears that were effusion-free as compared to 40 of 97 children (41.2%) in the amoxicillin group (P = 0.05). When considering all children with effusion-free ears as well as those "improved" from their original status (those with bilateral middle ear effusions at entry but only unilateral after treatment), 68 of 106 children (64.2%) receiving cefaclor were effusion-free or "improved," compared to 43 of 97 children (44.3%) receiving amoxicillin (P = 0.01). However, by 42 days after entry the percentage of children whose ears were without effusion or "improved" was equal in both treatment groups (68.9% in the cefaclor group and 67.5% in the amoxicillin group). The reasons for the differences observed at 14 days after entry are not readily apparent.