Tonsillectomy is one of the most common procedures performed in children, however there are currently no published studies evaluating tonsillectomy in children with 22q11.2 deletion syndrome (22q11DS). With this study, our goal was to investigate the indications, efficacy, and complications of tonsillectomy in a pediatric cohort of patients with 22q11DS. This is a retrospective chart review of patients in our 22q Center's repository. Inclusion criteria were a diagnosis of 22q11DS and a history of tonsillectomy or adenotonsillectomy. Data collected included: indications for tonsillectomy, preoperative and postoperative polysomnography (PSG) results, and surgical complications. In total, 33 patients were included. Most common indications for tonsillectomy were facilitation with speech surgery ( = 21) and sleep-disordered breathing (SDB)/obstructive sleep apnea (OSA) ( = 16). Average length of stay was 1.15 days. Most patients (69%) had some degree of persistent OSA on postoperative PSG. Complications occurred in 18% of patients and included respiratory distress, hemorrhage, and hypocalcemia. This study demonstrates tonsillectomy was a commonly performed procedure in this cohort of patients with 22q11DS. These data highlight the potential need for close postoperative calcium and respiratory monitoring. The data were limited with respect to PSG outcomes, and future studies are needed to better characterize OSA outcomes and complications in this patient population.