Four newer cephalosporins (cefazolin, cefamandole, SK&F 59962, and cefoxitin) were investigated for determination of their antistaphylococcal activity and relative stability to staphylococcal β-Iactamase (penicillinase). Crude preparations of βlactamase from recent clinical isolates of Staphylococcus aureus were used. Cefamandole and SK&F 59962 were highly active against both large and small inocula of staphylococci and were resistant to staphylococcal β-Iactamase. Cefoxitin, although resistant to β-lactamase, possessed less antibacterial potency but was still approximately as active as methicillin. Cefazolin was somewhat more susceptible to staphylococcal β-Iactamase than the other three agents and resembled cephaloridine in this respect. With minor exceptions, a correlation was found between the susceptibility of different agents to β-lactamase and the magnitude of the effect of inoculum size when the drugs were tested against large and small inocula of staphylococci.