Cefaclor, a new oral cephalosporin, was compared in vitro with cephalexin and cephradine against 233 organisms. Evaluations were performed in Mueller-Hinton and nutrient broth and agar using two inoculum sizes. In agar, cefaclor had greater antibacterial activity than either cephalexin or cephradine against isolates of Escherichia coli, Proteus mirabilis, Staphylococcus aureus, Klebsiella pneumoniae, and Salmonella typhi. All three drugs were relatively inactive against isolates of enterococci, Enterobacter species, and indole-positive Proteus. Cefaclor, however, did exhibit the greatest activity of the three antibiotics against these organisms. Although there was wide variability with respect to test parameters, the broth results generally paralleled the agar results. In nutrient broth a clear separation of the results with these three cephalosporins was seen with K. pneumoniae, E. coli, and S. typhi. Cefaclor was the most active, cephalexin had intermediate activity, and cephradine was the least active. From the data obtained in this in vitro study, it can be concluded that cefaclor, which has a substituted chloro group attached to the molecule, had increased antibacterial activity over cephalexin and cephradine. Comparative clinical trials with cefaclor will determine whether the differences outlined above are of clinical significance.