In vitro sensitivity tests indicate that cephalothin sodium is highly active against coagulase-positive penicillin resistant staphylococci, pneumo-cocci, and group A streptococci, and has significant activity against selected Gram-negative rods. Serial serum levels of cephalothin in volunteers after 1 gm intramuscular injections exceeded many-fold the in vitro minimum inhibitory concentrations for staphylococci, pneumococci, and group A streptococci. Clinical effectiveness of cephalothin against these organisms was confirmed by treatment of 51 patients with various severe infections. Cures were regularly obtained in those with infections due to staphylococci and pneumococci, whereas occasional impressive responses occurred in Gram-negative infections. Generally unfavorable treatment results were observed for mixed infections due to a staphylococcus plus a Gram-negative rod, or 2 or more Gram-negative rods. Successful cephalothin treatment of serious infection in 10 of 12 penicillin-allergic patients helps confirm the value of this agent in the presence of penicillin hyper-sensitivity.