Seventy-two adult patients with Staphylococcus aureus bacteremia were prospectively studied clinically, serologically, and echocardiographically. Multivariate analysis identified four parameters that significantly predicted endocarditis in staphylococcemic patients at time of initial evaluation: absence of a primary site of infection; community acquisition of infection; metastatic sequelae; and valvular vegetations detected by echocardiography. Echocardiography was most predictive of endocarditis in patients with community-acquired S aureus bacteremia from an obvious primary focus. In 11 (69%) of 16 patients with endocarditis and vegetations on two-dimensional echocardiography, this technique also revealed other important findings, including ventricular dilatation, and/or underlying valvular lesions. In 18% of patients with S aureus bacteremia without stigmata of endocarditis, echocardiography provided information that led to a diagnosis of endocarditis and a subsequent change in therapy. Our findings support the routine use of two-dimensional echocardiography in all cases of community-acquired S aureus bacteremia to identify occult endocarditis in patients without classic stigmata of disease, and to provide important prognostic data in clinically apparent endocarditis.