Two independent, investigator-blinded, multicenter, randomized clinical trials, one of which included microbiologic evaluation of middle-ear fluid obtained by use of tympanocentesis, compared the efficacy and safety of two oral antibiotics, cefuroxime axetil suspension and amoxicillin/clavulanate suspension, in the treatment of children 3 months to 12 years old diagnosed with acute otitis media with effusion (AOME). Four hundred seventy-seven pediatric patients with signs and symptoms of AOME were enrolled at 20 centers and were randomly assigned to receive 10 days of treatment with either cefuroxime axetil suspension 30 mg/kg per day in two divided doses (n = 235) or amoxicillin/clavulanate suspension 40 mg/kg per day in three divided doses (n = 242). Patients were assessed for their response to treatment once during treatment (at 3 to 5 days) and twice after treatment (at 1 to 4 days and at 14 to 18 days). In the study that included tympanocentesis, bacteriologic assessments were based on middle-ear fluid cultures obtained pretreatment, and, when possible, posttreatment in patients with an unsatisfactory clinical outcome. Organisms were isolated from the pretreatment middle-ear fluid specimens of 120 (73%) of 164 patients undergoing tympanocentesis, with the primary pathogens being Streptococcus pneumoniae. Haemophilus influenzae, and Moraxella catarrhalis (27%, 24%, and 6% of isolates, respectively). Forty-four percent of the H influenzae isolates and 94% of the M catarrhalis isolates that were tested for beta-lactamase production were positive. A satisfactory clinical outcome (cure or improvement) was obtained in 70% of clinically assessable patients treated with cefuroxime axetil or amoxicillin/clavulanate, respectively (P = 0.40). With respect to the eradication of bacterial pathogens, in the study that included tympanocentesis a satisfactory outcome (cure or presumed cure) was obtained in 84% (32 of 38) and 95% (36 of 38) of bacteriologically assessable patients treated with cefuroxime axetil or amoxicillin/clavulanate, respectively (P = 0.26). Treatment with amoxicillin/clavulanate was associated with a significantly higher incidence of drug-related adverse events than was treatment with cefuroxime axetil (37% vs 16%; P < 0.001), primarily reflecting a higher incidence of drug-related gastrointestinal adverse events (34% vs 12%; P < 0.001), particularly diarrhea. Eight patients in the cefuroxime axetil group and 11 patients in the amoxicillin/clavulanate group withdrew from the studies because of drug-related adverse events. These results indicate that cefuroxime axetil suspension 15 mg/kg twice daily is as effective as amoxicillin/clavulanate suspension 13.3 mg/kg three times daily in the treatment of pediatric patients with AOME, but produces fewer gastrointestinal adverse events, particularly diarrhea.