Objectives: To examine the sensitivity of contemporary transthoracic echocardiography (TTE) for the detection of vegetation, abscess cavity, or prosthetic valve dehiscence (Vg) in patients with suspected infective endocarditis (IE) and to identify whether a relatively normal initial TTE finding can be effectively used as a rule out test, obviating the need for transesophageal echocardiography (TEE). Patients and Methods: We evaluated clinical, microbiological, and echocardiographic data for all patients with suspected IE referred for both TTE and TEE between January 1, 2005, and December 31, 2010. Patients were stratified into 3 groups by baseline TTE findings: negative TTE (native valves with less than or equal to mild regurgitation and no Vg), equivocal TTE (no Vg but prosthetic valve or greater than mild native valvular regurgitation), and positive TTE (Vg detected). Results: We studied 622 consecutive patients (68% male; mean ± SD age, 62±17 years), including 256 with Staphylococcus aureus bacteremia (SAB). The presence of Vg was confirmed by TEE in 141 patients (23%). The TTE had low sensitivity for the detection of Vg (58%). A total of 271 patients (44%) had an initial negative TTE. Of these, TEE demonstrated Vg in only 8 patients (negative predictive value [NPV] of negative TTE, 97%). The negative TTE group included 132 patients with SAB, only 6 of whom had Vg (NPV, 95%). Of 265 patients with equivocal TTE, Vg was demonstrated in 51 (19%). Conclusion: In a hospital population with clinically suspected IE, TTE had low sensitivity for the detection of Vg; however, a negative initial TTE was a common finding, with a high NPV, even in the setting of SAB. A TEE may be avoided in many patients with suspected IE.