Staphylococcus aureus bacteremia often causes metastatic infection and endocarditis. The incidence of these complications in soft tissue-associated bacteremia is not well defined. We conducted a prospective observational study of all adult in patients with S. aureus bacteremia originating from soft tissues from 1 January 2002 to 30 June 2003, in a 600-bed teaching hospital. 376 patients with ≥1 positive blood cultures for S. aureus were encountered; 50 (13.3%) had a soft tissue source, and 46% were nosocomial. Age was 21-103 y (median 60 y). The majority (96%) had comorbid conditions. Predisposing factors such as surgery, trauma and miscellaneous skin conditions were common (88%). Oxacillin-resistant isolates accounted for 26 cases (52%). Metastatic infections were uncommon (6%). Duration of bacteremia was 1-13 d (median 1 d). Bacteremia persisted for 2-13 d in 11 (28.9%) patients; only 2 had apparent complications. Duration of treatment was 5-42 d (median 14 d); it was ≤15 d in 23/41 (56.1%) patients. Therapy was all intravenous (68%) or intravenous/oral (32%). Attributable mortality rate was 6% and relapse was encountered in 1/25 survivors (4%) with follow-up. These findings suggest that soft tissue-associated S. aureus bacteremia has a favorable prognosis with rapid clearance and infrequent metastatic infections. It may persist without an obvious complication. Oral therapy after a brief intravenous treatment appears safe and warrants further assessment.