The comparative in vitro activity of cefoxitin, piperacillin, cefotetan, and ceftizoxime was compared against 843 surgical microbial isolates. All compounds exhibited excellent activity against the streptococcal isolates. Antimicrobial activity was poor for Staphylococcus aureus and S. epidermidis. Cefotetan activity against the Enterobacteriaceae was comparable to ceftizoxime (greater than 95% susceptible). Resistance rates of 0, 1, 5, and 2% were observed with cefoxitin, piperacillin, cefotetan, and ceftizoxime against the anaerobic cocci and anaerobic gram-positive non-spore-forming rods. Ninety-six and ninety-nine percent of the clostridial strains were susceptible to cefotetan and piperacillin, respectively. Piperacillin, cefotetan, and ceftizoxime exhibited similar activity against Bacteroides fragilis (resistance less than 10%). Cefotetan and cefoxitin exhibited poor activity against Bacteroides distasonis, B. ovatus, and B. thetaiotaomicron. Antimicrobial activities were comparable for the four drugs against other Bacteroides and Fusobacterium species. The results demonstrate that all four compounds exhibited broad antimicrobial activity against facultative and obligate anaerobic surgical isolates from intraabdominal and soft tissue infections.