Objective To explore the possible causes and the appropriate management of liquefactive necrosis in ablative area after microwave ablation for thyroid nodules. Methods A total of 3 480 thyroid nodules treated with microwave ablation between Jan. 2008 and Dec. 2017 were followed up. The clinical data, treatment methods and outcomes of the patients with liquefactive necrosis in ablative area were analyzed retrospectively. Results Of the 3 480 thyroid nodules, 18 (0.52%) had liquefactive necrosis in ablative area after microwave ablation. The maximum diameters of the 18 (100.00%) thyroid nodules were all greater than or equal to 2.5 cm before microwave ablation, the locations were all closely adjacent to the thyroid capsule, blood flows surrounding the nodules were all blocked by microwave energy during ablative operation, and the counts and proportions of white blood cell in the peripheral blood were all normal after the occurrence of liquefaction. Eighteen patients with liquefactive necrosis in ablative area were all clinically cured. In 2 cases among them, the necrosis dissipated spontaneously after orally taking anti-inflammatory drugs without local treatment for the ablation area. Ten patients underwent surgical incision to remove the liquefactive necrotic substance in the ablation area, and the incision healed on 14-26 days; and 2 cases in them had obvious scar formation on the neck skin. Six patients underwent ultrasound-guided drainage to remove the necrosis, the subcutaneous sinus tract healed on 10-20 days, and all had no neck scar formation. Bacterial culture of liquefactive material was performed in 16 patients, and the results were all negative. Conclusion The liquefaction of coagulated necrotic tissue in the ablative area of thyroid nodules after microwave ablation is a sterile process, and may be related to the large size of nodules, the close location of nodules to the capsule and the thermal blockade of blood flow. The "liquefaction and absorption disequilibrium" hypothesis may provide clues for exploring its potential mechanism. Ultrasound-guided drainage by dilating the subcutaneous sinus can successfully remove the necrotic materials and avoid scarring of neck skin.