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The aim of this study was to investigate the ability of transthoracic echocardiography (TTE) to detect vegetations and the relationship between blood cultures and transesophageal echocardiography (TEE).Five hundred eleven TTE and TEE pairs performed to evaluate endocarditis were retrospectively analyzed. Vegetation on TTE, prosthetic valve, change in regurgitation, and blood cultures were correlated with vegetation on TEE.TTE detected 45% of vegetations seen on TEE. There was no difference for prosthetic valves. Prosthetic valves (odds ratio, 1.7; P = .03) and increased regurgitation (odds ratio, 1.7; P = .01) were associated with vegetations on TEE; staphylococcal bacteremia and fungemia were not. Negative blood cultures were associated with negative results on TEE (P < .0001), but 27% of patients with prosthetic valves had culture-negative endocarditis or nonbacterial thrombotic endocarditis, and 6% had abscesses missed by TTE.This study demonstrates a limited capacity of TTE to detect vegetations. TEE may be an appropriate initial study to evaluate prosthetic valves. TEE for culture-negative endocarditis deserves further study.