OBJECTIVE: This prospective observational cohort real-world study evaluates and compares the efficacy and prognosis of ultrasound (US) and gene-based microwave ablation (MWA) and surgical treatment in patients with low-risk papillary thyroid carcinoma (PTC), emphasizing the influence of genetic mutations on low-risk patient selection. BACKGROUND: MWA, a minimally invasive technique, is increasingly recognized in the management of PTC. While traditional criteria for ablation focus on tumor size, number, and location, the impact of genetic mutations on treatment efficacy remains underexplored. METHODS: A total of 201 patients with low-risk PTC without metastasis were prospectively enrolled. All patients underwent US and next-generation sequencing to confirm low-risk status. Patients chose either ablation or surgery and were monitored until November 2024. Efficacy and complications were assessed using thyroid US and contrast-enhanced US. RESULTS: The median follow-up of this study is 12 months. There is no significant difference between the ablation group (3.0%) and the surgery group (1.0%) in disease free survival ( CONCLUSIONS: For patients with low-risk genetic mutations, ablation provides comparable efficacy and disease free survival to surgery, with significant benefits in safety, recovery, and overall cost. Guided by US and next-generation sequencing, precise patient selection enhances the potential of ablation as a promising, minimally invasive alternative to surgery in the management of low-risk PTC .