Cefamandole and cefoxitin, introduced only 7 years ago, are now the most commonly prescribed parenteral antibiotics in the United States. These drugs are similar to the first-generation cephalosporins in toxicity, but their in-vitro spectrum of activity is greater. Their serum half-lives are longer than those of cephalothin and cephapirin but shorter than that of cefazolin. Although cefamandole has been recommended in empiric therapy for patients with community-acquired pneumonia and as a prophylactic agent for patients having various surgical procedures, other regimens are less expensive and just as effective. Cefamandole should not be used to treat intra-abdominal, enterobacter, or ampicillin-resistant Haemophilus influenzae infections. Cefoxitin is effective in the treatment and prevention of mixed aerobic-anaerobic skin and soft-tissue, intra-abdominal, gynecologic, and penicillinase-producing, spectinomycin-resistant Neisseria gonorrhoeae infections. Cefoxitin represents a greater advance than cefamandole in our continuing search for safe and more effective antimicrobial agents.