Objectives: The study aims to retrospectively summarize the clinical features of pediatric thyroglossal duct cyst (TGDC), investigate the efficacy of the modified Sistrunk (mSis) procedure, and analyze the recurrence risks. Methods: The clinical data of 391 children with TGDC admitted to Beijing Children’s Hospital affiliated Capital Medical University and Baoding Children’s Hospital from March 2012 to December 2021 were retrospectively analyzed. All patients underwent cervical ultrasound for preoperative evaluation. Twenty cases had magnetic resonance imaging and 8 cases had computed tomography for further evaluation. All patients underwent the standard mSis procedure, and clinical manifestations information, surgical information, complications, and prognosis were analyzed. Results: Among the 391 TGDC cases, 118 (30.2%) had a history of recurrent neck infection and 36 (9.2%) had undergone previous neck cyst and fistula resection surgeries, initially diagnosed as neck cyst (22 cases), TGDC (12 cases), or branchial fistula (2 cases), with only 6 cases having undergone partial hyoid bone resection in the previous operation. During the 15 to 156 months of follow-up, 10 children experienced local wound infection, but no other complications were reported. The recurrence rate was 2.30%, and the recurrence time ranged from 0.5 to 34 (average, 7.2) months post surgery. In the Poisson regression model examining factors related to recurrence, the P values of the 3 factors were <.05: clearness of the lesion boundary, surgical history, and maximum diameter and the relative risk (RR) values corresponding to the 3 risk factors, such as Exp (B), were 27.918, 10.054, and 6.606, respectively. Conclusions: The mSis procedure demonstrated safety and efficacy with fewer complications and a low recurrence rate of 2.30% in the study. Furthermore, the indistinct lesion boundary, surgical history, and large lesion diameter (>2 cm) were independent risk factors for recurrence in pediatric TGDC. Level of Evidence: IV