Background: Thyroid nodules are extremely common and are usually benign. 4%-6.5% of thyroid nodules are malignant. Among thyroid cancer investigations many diagnostic molecular biomarkers were found to have applications in thyroid nodules management and avoiding unnecessary thyroidectomy.(1) This study aims:To detect value of micro-RNA 221 expression in sera of patients with thyroid nodules and its relation to outcome after surgery. Patients and Methods: Forty-five adult subjects aged between 18 to 70-years old who were diagnosed with suspicious thyroid nodules that required total thyroidectomy were offered participation in the study. Based on the patient’s history, physical examination, US and FNAB findings patients who had thyroid nodules with U/S pattern suggestive of malignant potential (TIRADS score ≥ 3), also with indeterminate FNAB results (Bethesda III, IV) were selected. Samples of human serum were collected from the selected patients visiting the endocrine outpatient clinic and endocrine surgical department of Ain Shams University hospital. Results were correlated with postoperative pathology results. Results: In our study there was no significant difference regarding outcome in patients (benign or malignant) with respect to serum microRNA 221. There was a significant difference between benign and malignant outcomes regarding size of dominant nodules by ultrasound with a mean value equals 4.6 cm in largest dimension in patients with malignant thyroid nodules and p value equals 0.027 indicating increased size of nodule may be associated with increased risk of malignancy.