Purpose This study compared ethanol ablation (EA) with the Sistrunk operation (SO) with regard to feasibility, treatment efficacy, and cost-effectiveness. The goal was to evaluate whether EA could replace SO as a primary treatment modality for thyroglossal duct cysts (TGDCs). Methods This retrospective case-control study included patients with TGDCs who were treated with either EA or SO between 2016 and 2022. The primary outcome variables evaluated were treatment efficacy (as measured by the volume reduction rate [VRR] and treatment success rate), complications, and cost-effectiveness. Results A total of 72 patients were enrolled, with 33 in the EA group and 39 in the SO group. The procedure or operation times for the EA and SO groups were 9 and 82 minutes, respectively (P