Background: We aim to analyze the additive value of repeated transthoracic echocardiography (TTE) within a 1-week interval after a baseline TTE to diagnose infective endocarditis (IE) in patients admitted with Staphylococcus aureus bacteremia (SAB). Methods: We prospectively enrolled consecutive patients with SAB who were referred for TTE and transesophageal echocardiography (TEE) to exclude IE between January 2017 to December 2019. All patients underwent a second TTE within 5 to 7 days. We excluded patients with poor echo windows, previous IE, valve repair/replacement, and those with cardiac devices or a dialysis catheter in place. Results: A total of 105 patients were enrolled, of which 40 (38.1%) were female. The mean age was 52 ± 14 years.Sixty-four patients (61%) had a defined source of infection, and 36 (34.3%) were intravenous drug users. The majority (n = 74, 70.5%), had methicillin-sensitive S. aureus. Sixteen patients (15.2%) were diagnosed with definite IE based on TEE findings as follows: eight tricuspid valve IE, four mitral valve IE, three aortic valve IE, and one with double valve IE (mitral and tricuspid). The mortality rate was 7.6% (two patients with definite IE and six without IE). Vegetations were not detected in one patient on the first TTE, compared to TEE and the second TTE. The baseline TTE had a sensitivity of 93.8%, specificity of 87.6% and accuracy of 88.6% in identifying echocardiographic evidence of IE. The addition of second TTE findings increased the sensitivity to 100%, specificity to 95.5%, and diagnostic accuracy to 96.2% in comparison to TEE for the detection of IE. Conclusions A repeat TTE within 5 to 7 days of an initial study significantly enhances diagnostic accuracy for detecting IE in patients with SAB and may help reduce the need for TEE in selected low-risk cases.