Background The Prevalence of thyroid nodules is rising nowadays, luckily most of them are benign. The risk of malignancy 5-15%, which necessitates the ultimate need to accurately distinguish benign from malignant nodule to avoid unnecessary thyroidectomy with risk of recurrent laryngeal nerve injury, postoperative hypothyroidism and lifetime thyroid replacement therapy, and other complications related to surgery and anaesthesia. Recent evidence suggests that circulating miRNA might have probable advantage as diagnostic or prognostic markers for numerous cancers. Given their reproducible and constant presence in sera, miRNA profiles have emerged as a non-invasive method to categorise a wide variety of human cancers. Aim of the study To evaluate a possible relationship between the expression level of circulating miRNA-222 and the histological outcome of euthyroid patients undergoing thyroidectomy for thyroid nodules with indeterminate FNAB cytology. Patients and Methods 45 patients of both genders, of age ranging from 19-70 years old visiting endocrine clinic or admitted to the endocrine surgical department with indeterminate thyroid nodules planned for thyroidectomy were included. All pateints were subjected to full medical history taking, general and local clinical examination, laboratory investigations (thyroid function tests), quantitative assay of serum micro RNA-222 expression by quantitative Real-Time polymerase chain reaction (qRT-PCR), ultrasonography imaging of thyroid gland, fine needle aspiration biopsy and cytology of the thyroid nodule, histopathological examination after thyroidectomy. Results The incidence of thyroid nodules was predominant in female gender in benign group and malignant group. Risk of malignancy increases as TI-RADS and Bethesda scores increases. Also, larger nodule in size has a more risk of malignancy (p = 0.034). Expression level of circulating miRNA222 in serum can’t differentiate between healthy, benign and malignant patients where there was no significant difference between them statistically (p = 0.867). Circulating miRNA-222 is a poor predicator for malignant nodules with sensitivity of 50%, specificity of 32.43%, with high negative predictive value (NPV=75%). Conclusion Expression level of circulating miRNA-222 is a poor predictor of malignant nodules in our studied group. The larger the nodule size the more risk of malignancy. Also, as TI-RADS and Bethesda scores increases the more risk of malignancy.