Background: Echocardiography has been a popular modality used to aid in the diagnosis of infective endocarditis (IE) with the modified Duke criteria. We evaluated the necessity between the uses of either a transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) in patients with a body mass index (BMI) greater than or equal to 25 kg/m2 and less than 25 kg/m2. Methods: A single-centered, retrospective study of 198 patients between 2005 and 2012 diagnosed with IE based on modified Duke criteria. Patients, required to be above age 18, had undergone an echocardiogram study and had blood cultures to be included in the study. Results: Among 198 patients, two echocardiographic groups were evaluated as 158 patients obtained a TTE, 143 obtained a TEE, and 103 overlapped with TEE and TTE. Out of these patients, 167 patients were included in the study as 109 (65%) were discovered to have native valve vegetations on TEE and 58 (35%) with TTE. TTE findings were compared with TEE results for true negatives and positives to isolate valvular vegetations. Overall sensitivity of TTE was calculated to be 67% with a specificity of 93%. Patients were further divided into two groups with the first group having a BMI ≥25 kg/m2 and the subsequent group with a BMI <25 kg/m2. Patients with a BMI ≥25 kg/m2 who underwent a TTE study had a sensitivity and specificity of 54 and 92%, respectively. On the contrary, patients with a BMI < 25 kg/m2 had a TTE sensitivity and specificity of 78 and 95%, respectively. Conclusions: Patients with a BMI <25 kg/m2 and a negative TTE should refrain from further diagnostic studies, with TEE strong clinical judgment is warranted. Patients with a BMI ≥ 25 kg/m2 may proceed directly to TEE as the initial study, possibly avoiding an additional study with a TTE.