Semisynthetic penicillinase-resistant penicillins are recommended for therapy of Staphylococcus aureus endocarditis, but evaluation of the efficacy and safety of individual agents has received little attention. At The New York Hospital, 11 heroin addicts and 5 nonaddicts were treated with nafcillin. The 11 addicts did well clinically, but four of the five nonaddicts had severe complications, and three of them died. Important adverse reactions to nafcillin occurred in two patients: one developed leukopenia, and one developed an extensive rash. Methicillin was employed to treat two heroin addicts and four nonaddicts. Five of the six patients were cured bacteriologically, but three patients developed nephritis and one patient developed an extensive rash. Nafcillin appears to be highly efficacious for the treatment of S. aureus endocarditis, yielding results at least equal to those obtained with other drugs. Because adverse reactions appear to occur more frequently with methicillin than with nafcillin, we regard nafcillin as the preferable penicillinase-resistant penicillin for the treatment of S. aureus endocarditis.