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Objective: To assess risks and benefits of cardiac intervention in adults with Down syndrome (DS). Patients and Methods: A retrospective review was conducted using data from a study we published in 2010. Patients aged 18 years or older with DS who underwent cardiac operation or percutaneous intervention from February 2009 through April 2022 (new cohort) were compared with patients in the previous study (January 1969 through November 2007; remote cohort) at Mayo Clinic. Results: In total, 81 adults (43 men; 38 women) with DS underwent 89 cardiac interventions (84 surgical; 5 percutaneous) at a mean age of 33 years. Twenty-six patients presented with complete atrioventricular canal defect (17%) or tetralogy of Fallot (15%). The most common adult procedures were valve interventions: mitral (31%), tricuspid (15%), and pulmonary (12%). Of pulmonary valve interventions in the new cohort, 33% were performed percutaneously. The postoperative mortality rate was low (1% total). The mean time between last operation and death was 16 years. Conclusion: Adults with DS can undergo cardiac operation and percutaneous intervention with low morbidity and mortality risk and good long-term survival.