BACKGROUND: We examined the effect of genetic syndromes and extracardiac (GS/EC) anomalies on single-ventricle (SV) palliation with focus on hospital and interstage death and progression toward subsequent palliation stages. METHODS: First-stage palliation was performed in 530 neonates with SV: Norwood in 284 (53%), shunt in 173 (33%), and band in 73 (14%). Outcomes were compared between those with GS/EC anomalies (121 [23%]) and without GS/EC anomalies (409 [77%]). Regression analyses were adjusted for other risk factors (age, sex, prematurity, weight, SV anomaly, and first-stage palliation operation). RESULTS: GS/EC anomalies varied among SV defects (range, 3% for double-inlet left ventricle to 100% for atrial isomerism). Patients with GS/EC anomalies required significantly longer durations of mechanical ventilation and intensive care unit and hospital stay. Although patients had comparable rates of extracorporeal membrane oxygenation (13% vs 11%, p = 0.552) and unplanned reoperation (16% vs 11%, p = 0.189), hospital mortality was higher in patients with GS/EC anomalies (24% vs 12%, p = 0.0008). After discharge, patients with GS/EC anomalies had higher interstage death, with lower progression to Glenn (60% vs 77%, p = 0.002) and lower 10-year survival (56% vs 76%, p < 0.001). After adjustment for other risk factors, GS/EC anomalies significantly affected survival in almost all subgroups of patients. CONCLUSIONS: The presence of GS/EC anomalies varies among SV anomalies and is associated with additional risk factors such as prematurity and low weight. After adjusting for other risk factors, GS/EC anomalies are associated with prolonged recovery after first-stage palliation and increased hospital and interstage death, with subsequently fewer patients progressing toward Glenn shunt. The increased death risk in those patients is highest in the first 6 months and persists for 2 to 3 years after first-stage palliation, suggesting the need for more vigilant monitoring and outpatient care in these high-risk patients.