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Background: MicroRNAs are mentioned as a small non-coding RNAs groups and aberrant miRNA expression was found in hepatocellular carcinoma (HCC) patients. Aim: To evaluate role of plasma MicroRNA-215 as a diagnostic tool in HCC patients. Methods: A prospective study included 195 subjects: healthy controls (group I), cirrhotic patients (group II), and patients with HCC (group III). Clinical examination, radiological and laboratory investigations which included quantification of miR-215 by Real-time qPCR were done for all cases. Results: Spearman’s rank correlation revealed that in HCC group, there was a negative correlation between MiRNA-215 and serum AFP levels and focal size lesion (cm) (rs = -0.72, - 0.94 respectively, p<0.001). Receiver operating characteristics analysis for discrimination between cirrhosis and HCC groups regarding microRNA-215 displayed 78.3% sensitivity, 88.0% specificity at cutoff value of ≤ 1.90. Area under the curve (AUC) was 0.87 (p< 0.001). As regards AFP, it had a sensitivity of 81.7%, a specificity of 66.7 at cutoff value of ≥ 11.50 (ng/mL). Conclusions: Plasma level of miR-215 may be a promising biomarker in HCC diagnosis. Moreover, if miR-215 combined with AFP, it can be used as a diagnostic biomarker, for early detection of HCC.