Ceftibuten is a new oral cephalosporin with an unusual stability to beta-lactamases that can hydrolyze other extended-spectrum cephalosporins. Using the chinchilla animal model, we compared the efficacy of ceftibuten (n = 33) with that of saline (n = 34), ampicillin (n = 32), and cefixime (n = 31) for the treatment of acute otitis media caused by beta-lactamase-producing nontypeable Hemophilus influenzae. Ceftibuten was superior to ampicillin regarding the time necessary to sterilize the middle ear (p < .001) and eliminate effusion (p < .001). The mean days of therapy required for bacteriologic cure were 2.57 for ceftibuten, 2.95 for cefixime, 7.95 for ampicillin, and 8.16 for saline. At the conclusion of therapy, chinchillas treated with ceftibuten had a significantly lower prevalence of positive cultures and middle ear effusion than did animals treated with ampicillin. No significant differences were observed between ceftibuten and cefixime. The results of this randomized, investigator-blinded experiment warrant further consideration of ceftibuten as a second-line agent for acute otitis media caused by ampicillin-resistant H influenzae.