BACKGROUND Although echocardiography has been incorporated into the diagnostic algorithm of patients with suspected infective endocarditis (IE), systematic usage in clinical practice remains ill defined. To determine the diagnostic accuracy of detecting vegetations using harmonic transthoracic echocardiography (hTTE) as compared to transesophageal echocardiography (TEE) in patients with an intermediate likelihood of native valve IE. METHODS Between 2004 and 2005, 36 consecutive inpatients with an intermediate likelihood of disease were prospectively evaluated by hTTE and TEE. RESULTS Of 36 patients (21 males with a mean age of 57 +/- 15 years, range 32 to 86 years), 19 patients had definite IE by TEE. The sensitivity for the detection of vegetations by hTTE was 84%, specificity of 88%, positive predictive value (PPV) of 89% and negative predictive value (NPV) of 82%. The association between hTTE and TTE interpretation for the presence and absence of vegetations were high (kappa = 0.90 and 0.85 respectively). CONCLUSIONS In patients with an intermediate likelihood of native valve IE, TTE with harmonic imaging provides diagnostic quality images in the majority of cases, has excellent concordance with TEE and should be recommended as the first line test.