Background: Complications of Staphylococcus aureus bacteremia (SAB) are often difficult to identify. The ability to accurately predict the likelihood of these complications would impact patient management. This investigation sought to define readily available clinical characteristics that could help identify patients at risk for complicated SAB. Methods: A prospective, observational cohort study was conducted from September 1994 through December 1999. Patients were followed up for 12 weeks after the initial positive blood culture result. The primary end point was complicated SAB (attributable mortality, complicated infection, embolic stroke, or recurrent S aureus infection during the 12-week follow-up period). The predictive model was validated using bootstrap resampling. Results: Complicated SAB was present in 43% of 724 consecutive adult hospitalized patients identified during the study period. The full predictive model had a high discriminative ability (bootstrap-corrected c index, 0.78). The strongest predictor of complicated SAB was a positive follow-up blood culture result at 48 to 96 hours. A scoring system based on the presence or absence of 4 risk factors (community acquisition, skin examination findings suggesting acute systemic infection, persistent fever at 72 hours, and positive follow-up blood culture results at 48-96 hours) accurately identified complicated SAB (bootstrap-corrected c index, 0.76). Conclusion: Readily available clinical variables can help identify patients at risk for complicated SAB.