Transesophageal echocardiographic (TEE) guidance of cardioversion in patients with atrial fibrillation is an alternative method to conventional anticoagulation. Although TEE is considered the gold standard for excluding left atrial (LA) thrombi, in some patients dense spontaneous echo contrast (SEC) and artifacts may hamper the identification or exclusion of LA thrombi. Often those patients are refused cardioversion. The purpose of this study was to determine whether the application of echo contrast (Optison, Mallinckrodt, San Diego, Calif) facilitates the exclusion of LA appendage thrombi in this patient group and allows for safer cardioversion. Forty-one patients with atrial fibrillation and dense SEC or inconclusive TEE findings were given echo contrast. Fourteen patients with sinus rhythm served as control participants. Echo contrast completely reduced artifacts in 13 of 22 patients. In 12 of 19 patients with SEC, the LA appendage was completely filled after the application of echo contrast and, thus, SEC was completely suppressed. In 13 of 41 patients, it was filled incompletely and in 9 of 41 patients, a new mass resembling a thrombus was detected. In total, of 25 of 41 patients with inconclusive TEE findings an atrial thrombus was definitively excluded. Those patients underwent cardioversion. None of those patients had a cerebral embolic complication as assessed by cranial magnetic resonance imaging. Thus, the application of echo contrast may facilitate the TEE exclusion of LA appendage thrombi and, hence, improve the safety of TEE-guided cardioversion.