BACKGROUND: Ultrasound enhancing agents (UEAs) are an important diagnostic tool for transthoracic or stress echocardiography (TTE/SE) but recent concerns have been raised about their safety in reports from individual health systems. As such, we aimed to identify if UEAs for TTE/SE are associated with serious adverse events within 2 days of administration. METHODS AND RESULTS: All-payor nationwide claims from 11.4 million insured individuals across the United States, 2018 to 2022 were used to evaluate rates of death, anaphylaxis, myocardial infarction, ventricular tachycardia, or cardiac arrest within 2 days of TTE/SE among adults receiving and not receiving UEAs. Of the 11 421 463 individuals included (mean age 57.5±16.2, 54.0% female, 46.2% White), a total of 500 073 (4.4%) received TTE/SE with UEAs. After propensity score matching, the odds of death were lower in those receiving UEAs (receipt versus nonreceipt, 0.02% versus 0.14%, odds ratio [OR], 0.23 [95% CI, 0.19-0.28], <0.001) and were not different across agents (Definity: 0.02%, OR, 0.22 [95% CI, 0.18-0.28]; Lumason: 0.03%, OR, 0.33 [95% CI, 0.20-0.57]; Optison: 0.01%, OR, 0.17 [95% CI, 0.08-0.38]; all  < 0.001). Rates of nondeath outcomes were similar to those observed in individuals not receiving UEAs, overall, and across specific agents. Rates of all outcomes were stable across years, including considering pre- and post-COVID periods. CONCLUSIONS: In this large nationwide claims analysis from 2018 to 2022, serious adverse events associated with UEAs for TTE/SE were uncommon and overall consistent across agents and years of study. Compared with nonreceipt, receipt of UEAs was associated with a lower odds of death within 2 days of TTE/SE.