We performed a retrospective study of a large cohort of patients who had episodes of Staphylococcus aureus bacteremia (SAB) from January 1995 through February 1999 at 1 medical center to identify predictors of 30-day mortality in SAB. Among 293 patients with episodes of SAB, 68 died (23.2%) within 30 days of onset. There was no significant difference in 30-day mortality associated with treatment with vancomycin, a beta-lactam, or a miscellaneous group of antimicrobial agents (P=.180). By logistic regression, an acute physiology score (a component of the acute physiology and chronic health evaluation [APACHE III]) >60 at onset of SAB was the most important predictor of 30-day mortality (odds ratio [OR], 15.7). Other significant predictors were lung (OR, 5.8) or unknown (OR, 4.1) focus of SAB, age > or =65 years (OR, 2.0), and diabetes mellitus (OR, 2.4). Future investigators of SAB should take into consideration acute severity of illness at onset as well as other factors when evaluating or comparing outcomes.