To evaluate whether having congenital heart disease (CHD) mediates community engagement, neuropsychiatric conditions, and quality of life (QOL) in adults with Down syndrome (DS). Cross-sectional survey of adults ages 18-45 years with DS and their caregiver, identified from NIH DS Registry, regional DS groups, and Cardiology clinics. The study survey consisted of adapted instruments (validated or prior use in this cohort) assessing medical history, employment/volunteer experience, QOL, mental health, and caregiver burden. Primary outcome was employment. Outcomes were compared between DS groups with and without CHD via Chi-squared test, t tests, and two proportion Z tests as appropriate. 287 subjects completed the study. Adults with DS and CHD (n = 104, 36%) reported similar employment rates as those without CHD: 61% and 60%, respectively (p = 0.87). Current volunteerism was significantly higher in DS + CHD subjects (32%) compared to DS alone (19%); p = 0.01. There were higher rates of stroke and seizure in DS + CHD (p < 0.01 for both), although no significant difference in psychological comorbidities (p = 0.67). 69% of all DS adults reported mental health problems. Proxy-reported mean QOL scores were similar between DS groups (p = 0.52). Mild-moderate caregiver burden was reported in both groups, with significantly greater burden reported in guardians of DS + CHD (p = 0.03). CHD is not associated with reduced employment or community engagement in adults with DS, despite significantly greater neurologic comorbidities. Similar QOL and mental health issues were reported in adults with DS regardless of having CHD. Findings may convey optimism to families of children born with both health issues.