To evaluate the clinical effect, safety, and clinical outcomes of focused transesophageal echocardiography (TEE) in the evaluation of critically ill patients in the emergency department (ED) and ICUs. We established a prospective, multicenter, observational registry involving adult critically ill patients in whom focused TEE was performed for evaluation of out-of-hospital cardiac arrest (OHCA), inhospital cardiac arrest, evaluation of undifferentiated shock, hemodynamic monitoring, and/or procedural guidance in the ED, ICU, or operating room setting. The primary objective of the current investigation was to evaluate the clinical influence and safety of focused, point-of-care TEE in critically ill patients. Data elements included patient and procedure characteristics, laboratory values, timing of interventions, clinical outcomes, and TEE video images. A total of 1,045 focused TEE studies were collected among 916 patients from 28 hospitals, including 585 (64%) intraarrest and postarrest OHCA and inhospital cardiac arrest, 267 (29%) initial evaluation of undifferentiated shock, 101 (11%) procedural guidance, and 92 (10%) hemodynamic monitoring. TEE changed management in 85% of patients with undifferentiated shock, 71% of patients with inhospital cardiac arrest, and 62% of patients with OHCA. There were no reported esophageal perforations or oropharyngeal injuries, and other procedural complications were rare. A prospective, multicenter, and multidisciplinary TEE registry was successfully implemented, and demonstrated that focused TEE is safe and clinically impactful across multiple critical care applications. Further studies from this research network will accelerate the development of outcome-oriented research and knowledge translation on the use of TEE in emergency and critical care settings.