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. This study aimed 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 FNAC. This study included 45 euthyroid patients with inderteminate thyroid nodules diagnosed with ultrasound and FNAC which planed for thyroidectomy. Quantitative assay of serum micro RNA-222 expression by quantitative Real-Time polymerase chain reaction (qRT-PCR) performed preoperatively, and results compared with postoperative histopathology. 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= 0.027). Expression level of circulating miRNA-222 in serum can’t differentiate between benign and malignant patients where there was no significant difference between them statistically (p=0.905). Circulating miRNA-222 was a poor predicator for malignant nodules with sensitivity of 50%, specificity of 32.43%, with high negative predictive value (NPV=75%). Conclusion: Although circulating miRNA-222 has been identified as novel minimally invasive biomarker for preoperative prediction of malignant nodules, but in our study, it did not show a value as a tool for discrimination of malignant nodules. Ultrasound remained important procedure in preoperative prediction and management of thyroid nodules especially when correlating to nodule size which had positive correlation with malignancy in our study