The long-term outcome of compliance with standard treatment recommendations for Staphylococcus aureus bacteremia was assessed. Cases of S. aureus bacteremia at our institution over a 2-y period were reviewed and follow-up performed by review of subsequent admissions or contact with primary care physicians. We encountered 226 cases (age 64.7 +/- 15.8 y) and most (171/226, 75.7%) had no removable source. In-hospital mortality rate was 32.7% (74/226). Follow-up of 104/152 (68.4%) survivors (for 386.7 +/- 449.8 d) revealed 23.1% (24/104) relapses: recurrent bacteremia (n = 19), distant site (n = 3) and local recurrence (n = 2). Most relapses (21124; 87.5%) occurred within 90 d of therapy. Relapse rate was higher with vancomycin treatment (20148 vs. 4/56; p < 0.001), bacteremia for > or = 3 d (9/20 vs. 15/84; p = 0.001), and failure to remove the source (6/7 vs. 6/22; p = 0.006). Vancomycin effect was independent of oxacillin susceptibility. Treatment for less than the standard 2-week duration among 19 patients with short duration of bacteremia (< 3 d) did not increase relapse rate (1/19; 5.3%). Duration of bacteremia, vancomycin therapy and failure to remove the source were predictors of relapse. Prospective studies are needed to determine if S. aureus bacteremias of short duration can be treated for 2 weeks or less, and define the optimal duration for prolonged bacteremia when vancomycin is used.