To compare the in vitro activity of cefamandole with ampicillin, cefoxitin, and gentamicin, each antimicrobial was tested against 419 bacteria isolated from the blood of patients with proved sepsis. Cefamandole was active against all gram-positive cocci except the enterococci. Most Enterobacteriaceae were inhibited by both cefamandole and cefoxitin. Cefamandole showed an activity similar to ampicillin against Haemophilus influenzae. The percent of blood culture isolates considered susceptible to the drugs tested were as follows: cefamandole 79%, cefoxitin 78%, ampicillin 55% and gentamicin 81%. None of the drugs tested would be adequate alone for treatment of sepsis of unknown etiology based on in vitro susceptibility data.