OBJECTIVE: To investigate whether a change in current treatment practice for Staphylococcus aureus bacteremia from flucloxacillin and aminoglycoside to flucloxacillin and fusidic acid was associated with any changes in outcome. METHODS: A retrospective analysis was carried out of 316 episodes of S. aureus bacteremia diagnosed and treated in a tertiary hospital complex between 1983 and 1993. Outcomes considered were (1) death related to the infection and (2) relapse following cessation of antibiotic therapy. RESULTS: Mortality related to infection, which occurred in 24% of patients, was unrelated to treatment with the combination of flucloxacillin and fusidic acid; however, increasing age was a significant risk factor (OR per decade=1.35, 95% CI=1.18-1.55), and increasing duration of treatment (OR per week of treatment=0.63, 95% CI=0.52-0.77), use of flucloxacillin (OR=0.30, 95% CI=0.14-0.64), presence of an intravascular device (OR=0.39, 95% CI=0.20-0.78) and presence of a skin lesion (OR=0.51, 95% CI=0.26-0.99) were significant protective factors. The only factor significantly related to relapse, which occurred in 11% of patients, was treatment with the combination of flucloxacillin and fusidic acid (OR=0.32, 95% CI=0.12-0.85). There was approximately a 70% reduction in the risk of relapse if this combination was used. CONCLUSIONS: This retrospective analysis suggests a clinically important protective effect of fusidic acid against relapse in patients with S. aureus bacteremia. Although the results were adjusted for potential confounding factors, the possibility of bias remains. There is a need for a prospective randomized trial to evaluate the effectiveness of flucloxacillin and fusidic acid for treating S. aureus bacteremia.