Objectives We evaluated the short- and long-term safety of contrast agents during stress echocardiography (SE). Background Concerns about contrast agent safety led to revised recommendations for product use in the U.S. Methods We studied 26,774 patients who underwent SE between November 1, 2003, and December 31, 2007. The 10,792 patients who comprised the contrast cohort received second-generation perfluorocarbon-based agents for left ventricular opacification during SE. The noncontrast cohort comprised 15,982 patients who had their first SE in the same period but without contrast agents. Short-term (≤72 h and ≤30 days) and long-term (up to 4.5 years) end points were death and myocardial infarction (MI). Cox regression models were used. Immediate contrast agent-related adverse effects were also reported. Results The contrast cohort had older patients (mean SD age, 65.8 12.1 years vs. 62.6 14.1 years; p < 0.001), a higher percentage of males (57.4% vs. 52.8%, p < 0.001), and higher-risk patients compared with the noncontrast cohort. In addition, dobutamine SE patients had greater cardiac risk than exercise SE patients. Abnormal SE findings in patients who received contrast agents were more frequent (32.4% vs. 27.9%, p < 0.001). The 2 cohorts had no statistical difference in the incidence of short-term events (death and MI). Within 72 h, 1 patient in the contrast cohort and 2 patients in the noncontrast cohort died (p = 0.54); 3 in the contrast cohort and 7 in the noncontrast cohort had MI (p = 0.92). Within 30 days, 37 patients (0.34%) in the contrast cohort and 57 patients (0.36%) in the noncontrast cohort died (p = 0.85); 17 patients (0.16%) in the contrast cohort and 16 patients (0.10%) in the noncontrast cohort had MI (p = 0.19). Adjusted hazard ratios were not different between cohorts for death (0.99; 95% confidence interval: 0.88 to 1.11) or MI (0.99; 95% confidence interval: 0.80 to 1.22). Conclusions The use of contrast agents during SE was not associated with an increased short-term or long-term risk of death or MI.