Background: Infective endocarditis (IE) is a serious complication of Staphylococcus aureus bacteremia (SAB). There is limited clinical evidence to guide use of echocardiography in the management of SAB cases. Methods: Baseline and 12-week follow-up data of all adults hospitalized at our institution with SAB from 2006 to 2011 were reviewed. Clinical predictors of IE were identified using multivariable logistic regression analysis. Results: Of the 757 patients screened, 678 individuals with SAB (24% community acquired, 56% healthcare associated, and 20% nosocomial) met study criteria. Eighty-five patients (13%) were diagnosed with definite IE within the 12 weeks of initial presentation based on modified Duke criteria. The proportion of patients with IE was 22% (36/166) in community-acquired SAB, 11% (40/378) in community-onset healthcare-associated SAB, and 7% (9/136) in nosocomial SAB. Community-acquired SAB, presence of cardiac device, and prolonged bacteremia (≥72 hours) were identified as independent predictors of IE in multivariable analysis. Two scoring systems, day 1 (SAB diagnosis day) and day 5 (when day 3 culture results are known), were derived based on the presence of these risk factors, weighted in magnitude by the corresponding regression coefficients. A score of ≥4 for day 1 model had a specificity of 96% and sensitivity of 21%, whereas a score of <2 for day 5 model had a sensitivity of 98.8% and negative predictive value of 98.5%. Conclusions: We propose 2 novel scoring systems to guide use of echocardiography in SAB cases. Larger prospective studies are needed to validate the classification performance of these scoring systems.