We sought to prospectively evaluate the clinical application of the American College of Cardiology Foundation/American Society of Echocardiography Appropriateness Criteria (AC) for transthoracic echocardiography in a single-center university hospital. Indications for transthoracic echocardiograms (TTE) were prospectively determined for consecutive studies by 2 reviewers and categorized, according to the AC for TTE, as appropriate (A) or inappropriate (I). The overall level of agreement in characterizing appropriateness between reviewers was high (kappa = 0.83). Among the 1,553 studies for which a primary indication was determined, 89% were covered in the AC for TTE. Of these studies, 89% were A, and 11% were I. New important TTE abnormalities were more common on A compared with I studies (40% vs. 17%, p < 0.001), and noncardiac specialists more frequently ordered I studies (13% vs. 9%, p = 0.04). In conclusion, the AC for TTE encompasses the majority of clinical indications for TTE and appears to reasonably stratify TTE ordering. However, revisions will be needed to fully capture and stratify appropriate clinical practice.