Cefpirome, cefotaxime, ceftazidime, cefoperazone, ceftizoxime, and ceftriaxone were tested against approximately 6000 fresh clinical isolates from five medical centers. For 3031 strains of Enterobacteriaceae tested, cefpirome consistently had the lowest MIC50s and lowest percentage of resistant strains. Cefpirome was also the most active agent against the 2138 Gram-positive cocci tested; Staphylococcus haemolyticus was uniformly resistant to all agents tested. Against 791 nonenteric Gram-negative bacilli, the activity of cefpirome was most comparable to that of cefoperazone and slightly less active than ceftazidime. Among the current third-generation cephalosporins, cefotaxime and cefoperazone emerged as having better overall balanced activity. Ceftazidime displayed poorest coverage against Enterobacteriaceae and Gram-positive organisms. Ceftizoxime also provided compromised coverage of staphylococci and nonenteric Gram-negative bacilli. Cefpirome remains as active as originally described in 1984 and possesses a slightly wider spectrum of activity against contemporary aerobic pathogens compared to currently marketed third-generation cephalosporins.