The in vitro activities of cefditoren and 8 other oral agents were compared against 262 clinical isolates representing major pathogens of the respiratory tract. Cefditoren was the most active agent overall in terms of its overall activity against Enterobacteriaceae, Haemophilus influenzae, and gram-positive pathogens. The activity of cefditoren was greatest against the types of pathogens likely to be encountered in outpatient settings, including streptococci, H. influenzae, Enterobacteriaceae that produced narrower-spectrum β-lactamases and low-level AmpC β-lactamases, and methicillin-susceptible Staphylococcus aureus. It was significantly less active against the types of Enterobacteriaceae likely to cause nosocomial infections in hospitals with resistance problems, including isolates that produce extended-spectrum β-lactamases or high-level AmpC β-lactamases. Cefditoren was significantly more resistant to hydrolysis by β-lactamases than cefprozil, loracarbef, and penicillin. Based on these attributes, cefditoren warrants further investigation as an anti-infective agent for use against a wide range of pathogens.