By investigating the predictors of malignancy in Bethesda III and IV-classified thyroid nodules, we found that age equal to or more than 40 years, higher body mass index (BMI), history of previous radiation exposure, higher TSH, positive anti-TG antibodies, and sonographic features including the presence of solitary nodules, nodules with size >2 cm, marked hypoechogenicity, irregular borders, microcalcifications, ill-defined margins, and the presence of suspicious lymph nodes were significantly associated with increased malignancy risk. This evidence concerns the gene TG and thyroid nodule.