Background: Midazolam is a broadly used drug that can enhance tolerance to transesophageal echocardiography (TEE) in patients with cardiac conditions. Adverse reactions to midazolam have been described previously. We describe central-nervous side effects in 6 of 104 consecutive patients. Methods: One hundred four patients undergoing TEE-diagnostic procedure were investigated. TEE was performed using a SSA 360 Power Vision ultrasound unit (Toshiba, Tokyo, Japan) and a 5- to 6-MHz probe. Indication for TEE was evaluation of cardiac valves (6), search for cardiac embolism (23), patent foramen ovale or atrial septum defect (20), left ventricular dysfunction (11), aortic dissection (7), and other (37). Midazolam and, if necessary, the benzodiazepine antagonist flumazenil (0.25-0.5 mg) were administered intravenously. Results: The mean cumulative dose of midazolam administered in small fractions was 4.8 ± 2 mg. In 6 of 104 patients (5.7%) clinically significant adverse effects to midazolam occurred. The reactions were aggressiveness, euphoria, depression, and intense hiccups (singultus) despite low doses of midazolam. The severest forms of these adverse effects to midazolam could be successfully treated with intravenous infusion of flumazenil (0.25-0.5 mg intravenously). Conclusion: Adverse effects including aggressive, euphoric, or depressive behavior can occur in a significant proportion (6%) of patients with cardiac conditions undergoing TEE after intravenous administration of midazolam. The administration of the benzodiazepine antagonist flumazenil can reverse the adverse effects to midazolam successfully. (J Am Soc Echocardiogr 2002;15:1297-1300.)