The in vitro activity of a new oral cephalosporin, ceftibuten, was determined against 837 clinical isolates by agar dilution technique and compared with that of the oral cephalosporins, cefaclor, cefuroxime, cefixime, cefpodoxime, and cefprozil. Against Enterobacteriaceae, ceftibuten was the most active of the compounds. Ceftibuten MIC90s were less than or equal to 0.25 micrograms/ml for most members of the family Enterobacteriaceae, 0.13 microgram/ml for Haemophilus influenzae, 4 micrograms/ml for Moraxella catarrhalis, and 0.5 microgram/ml for Neisseria gonorrhoeae. Ceftibuten also was active against beta-haemolytic streptococci (serogroups A, C, and G) and penicillin-susceptible strains of Streptococcus pneumoniae (MIC90, 4 micrograms/ml), but was not active against Staphylococcus spp. or the anaerobic bacteria studied. Cefpodoxime and cefuroxime were the most active of the cephalosporins against nonenteric streptococci; cefprozil and cefuroxime were the most active against staphylococci, and cefaclor demonstrated the greatest activity against some Bacteroides spp. Most strains of Acinetobacter baumanii, Pseudomonas spp., and methicillin-resistant staphylococci, as well as all strains of Clostridium difficile, were resistant to each of the cephalosporins tested.