Trisomy 21 (T21) is the most common chromosomal abnormality, and is frequently associated with congenital heart disease. Results of previous studies evaluating the effect of T21 on postoperative outcomes and complications following heart surgery have been mixed. Our goal was to determine if T21 is associated with higher frequency of adverse postoperative outcomes following repair of tetralogy of Fallot (TOF). A query of the Pediatric Health Information System was performed for patients who underwent complete repair of TOF from 2004 to 2015. Patients with a genetic syndrome other than T21 and tracheostomy and/or gastrostomy prior to heart surgery were excluded. Two groups were created on the basis of whether patients received a diagnostic code for T21. The adverse outcomes of interest were postoperative mortality, postoperative length of stay (LOS), postoperative gastrostomy, and postoperative tracheostomy. Univariate and Kaplan–Meier analysis were performed to evaluate outcomes. There were a total of 4790 patients; 430 (9%) patients had T21, and 4360 (91%) patients without a genetic diagnosis. There was no significant difference in mortality before discharge between those with and without T21 (2.3% vs 1.4%; p = 0.155). Patients with T21 had longer postoperative LOS (mean of 19.8 days vs 12.4 days; p < 0.001), and higher rates of postoperative gastrostomy (13.3% vs 5.3%; p < 0.02). There was no significant difference between groups for rates of postoperative tracheostomy (1.9% vs 1.2%; p = 0.276). Kaplan–Meier analysis confirmed that patients with T21 had longer postoperative LOS and greater incidence of gastrostomy.