Infective endocarditis (IE) is the fourth leading cause of life-threatening infection in the UnitedStates and imposes significant morbidity and mortality. The American Heart Association guidelines for the diagnosis and treatment of IE do not address continuous-infusion (CI) oxacillin. This retrospective study compares outcomes between CI oxacillin and intermittent-infusion (II) oxacillin in the treatment of IE caused by methicillinsusceptible Staphylococcus aureus (MSSA). A total of 709 medical records were reviewed for inpatients with definitive IE treated between 1 January 2000 and 31 December 2007. Continuous data were analyzed by Student's t test or the Wilcoxon rank sum test. The chi-square test or Fisher's exact test was used to compare nominal data. A multivariate logistic model was constructed. One hundred seven patients met eligibility criteria for inclusion into the study. Seventy-eight patients received CI oxacillin, whereas 28 received II oxacillin. CI and II groups were similar with respect to 30-day mortality (8% versus 10%, P ؍ 0.7) and length of stay (20 versus 25 days, P ؍ 0.4) but differed in 30-day microbiological cure (94% versus 79%, P ؍ 0.03). Sixty-three patients received synergistic gentamicin, whereas 44 did not. The gentamicin and no-gentamicin groups were similar with respect to 30-day mortality (11% versus 4%, P ؍ 0.2) and 30-day microbiological cure (90% versus 89%, P ؍ 0.8); however, times to defervescence (4 versus 2 days, P ؍ 0.02) were significantly different. CI oxacillin is an effective alternative to II oxacillin for the treatment of IE caused by MSSA and may improve microbiological cure. This convenient and pharmacodynamically optimized dosing regimen for oxacillin deserves consideration for patients with IE caused by MSSA.Infective endocarditis (IE) is the fourth leading cause of life-threatening infection in the United States and imposes significant morbidity and mortality (2). Staphylococcus aureus now exceeds viridans group streptococci as the leading cause of IE in much of the developed world, including the United States, and IE caused by S. aureus has been shown to be an independent predictor of increased mortality (4, 9). Overall, mortality from IE remains as high as 40% in some series, and complications of IE, such as congestive heart failure, extracardiac infections, and thromboembolic events, occur more often with IE caused by S. aureus than with IE caused by other pathogens (1, 9, 11, 15-17). The American Heart Association (AHA) has recently issued evidence-based guidelines for the diagnosis and treatment of patients with IE, which recommend intermittent-infusion (II) oxacillin at 12 g daily divided every 4 to 6 h for up to 6 weeks for treatment of IE caused by methicillin-susceptible S. aureus (MSSA) (1). Although data for continuous-infusion (CI) oxacillin are lacking, oxacillin exhibits time-dependent bactericidal activity, has a short postantibiotic effect against MSSA, and has been promoted as an alternative to II oxacillin, which maximizes bacteri...