Cefotaxime and its desacetoxymethyl derivative, ceftizoxime (previously known as FK749), are both extremely active against a wide spectrum of bacteria. In the present comparative study, the activity of ceftizoxime exceeded that of cefotaxime by a factor of four or more for strains of Klebsiella, Enterobacter, Providencia, Serratia, and Bacteroides; the only species for which the activity of cefotaxime exceeded that of ceftizoxime by a factor of four was Vibrio cholerae. Against other species, the activity of the two drugs was roughly comparable. Both showed outstanding activity against Haemophilus influenzae and Neisseria gonorrhoeae. Comparative turbidimetric and morphological studies revealed that ceftizoxime was able to induce spheroplast formation and rapid lysis in Escherichia coli strains at lower concentrations than cefotaxime. This difference was not found, however, when E. coli strains resistant to ampicillin by an intrinsic (nonenzymic) mechanism were tested.