The discovery of penicillinase-resistant penicillins is an important landmark in the history of antibacterial chemotherapy. Methicillin came into clinical use in 1960, and its value in the treatment of penicillin-resistant staphylococcal infection is now well established. The same is true of the isoxazolyl penicillins, oxacillin and cloxacillin, which came on to the scenes about a year later. Numerous other penicillinase-resistant penicillins have now been synthesized. Preliminary studies of two of these, nafcillin (Rosenman and Warren, 1961 ; Yurchenco et al., 1961) and ancillin (Dolan, Bondi, et at., 1961 ; Dolan, Rhodes, et al., 1961 ; and Farquhar et al., 1962) were reported at the First Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago in 1961. Later a report on a third, quinacillin, appeared (Richards et al., 1963). In addition, it has been shown that derivatives of cephalosporin C are resistant to staphylococcal penicillinase while in many other ways resembling the penicillins. The nucleus of cephalosporin C, 7-aminocephalosporanic acid, which has now been isolated, is closely related to the penicillin nucleus, 6-aminopenicillanic acid, but differs from the latter in having a fused dihydrothiazine /3-lactam ring instead of a fused thiazolidine 83-lactam ring. A series of compounds have been prepared by adding different side-chains, as with the semisynthetic penicillins. Several of these have high activity against most penicillin-sensitive bacteria and the penicillinaseproducing staphylococci, and also moderate activity against some coliform bacilli. Studies of one of these, cephalothin, were reported at the Second Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago in 1962 (Anderson and Petersdorf, 1962 ; Walters et al., 1962). The present investigation is a comparative study of the antibacterial activity of the five penicillinase-resistant penicillins mentioned above, together with cephalothin and the thienylacetamido cephalosporanic acid in which the acetoxy 3 has been replaced by a pyridine group.