The activity of cefamandole was comparable to that of cephalothin, cefazolin, and cephaloridine against Staphylococcus aureus, Streptococcus pyogenes, and Diplococcus pneumoniae. In contrast, cefamandole was considerably more active than cephalothin, cefazolin, or cephaloridine against gram-negative facultative bacilli, including Haemophilus influenzae, the most striking disparities being noted with indole-positive Proteus and Enterobacter. Bacteroides fragilis was more susceptible to cefoxitin than to cefamandole or cefazolin (median minimal inhibitory concentration, approximately 8, 32, and 32 mug/ml, respectively); cephalothin exhibited still less activity against this species. The majority of other anaerobes were inhibited by relatively low concentrations of all four cephalosporins. The results indicate a potentially valuable role for cefamandole against facultative gram-negative bacilli, including H. influenzae, but no exceptional activity against anaerobes.