Introduction Ultrasound enhancing agents (UEAs) are often utilized to enhance ultrasound image quality; however, concerns about adverse reactions have limited their use. Moreover, these agents had been either contraindicated or are labeled with a warning in patients with intra‐cardiac shunts because of a theoretic risk of systemic microvascular obstruction. This labeling was recently removed in the United States, but data in these patients are lacking. Methods Over a 15‐month period, patients receiving three different FDA‐approved UEAs at our center were prospectively evaluated for clinically significant adverse events (AEs). Results A total of 5521 UEA administrations were performed (Definity®: 3306, Lumason®: 2137, Optison®: 78). There were 14 AEs (0.25%) reported (Lumason®: 0.05% [n = 1] vs Definity®: 0.39% [n = 13], P = 0.02). Back pain was the most common complaint (n = 9), followed by headache (n = 2), rash (n = 2), dyspnea (n = 2), and palpitations (n = 1). Among the 33 patients known to have intra‐cardiac shunts, there were no AEs. Known right‐to‐left shunts with positive saline bubble study were present in 20 patients (Lumason®: n = 9, Definity®: n = 11). Left‐to‐right atrial shunts based on color Doppler were present in 10 patients (Lumason®: n = 5, Definity® n = 5). Three patients were known to have ventricular septal defect with left‐to‐right flow (Definity®: n = 2, Optison®: n = 1). Conclusion Adverse events were significantly higher with Definity®; however, overall incidences were low, and AEs were minor. Furthermore, no AEs were reported in patients with known intra‐cardiac shunts. UEAs showed a good safety profile in our study and should be afforded to all appropriate patients, including those with known intra‐cardiac shunts.