Staphylococcus aureus is the commonest cause of acute endocarditis in intravenous drug abusers. In-vitro and in-vivo animal studies have found increased killing of organisms with the combination of a beta-lactam antibiotic and an aminoglycoside. These findings have created a controversy about the use of such combination therapy. We randomly treated 25 episodes of S. aureus endocarditis in intravenous drug abusers with either single or combination antibiotic regimens. Mean days to defervescence were similar in both groups: 6.3 d (SEM, 1.49 d) for the single drug group and 6.6 d (SEM, 1.02 d) for the group treated in combination with an aminoglycoside. There were no bacteriologic failures or relapses in either group. No patients needed valvular surgery, and the mortality rate was zero. Thus, it appears that single drug therapy with an appropriate beta-lactam antibiotic is adequate and appropriate in intravenous drug abusers with S. aureus endocarditis.