Objective: To investigate the leveles of miRNA-122 and miR-221 in the serum of HCC patients, and explore the value of miR-122 plus miR-221 detections on hepatocellular carcinoma(HCC) diagnostic performance. methods：39 HCC patients and 40 healthy volunteers were recruited from Affiliated Hospital of NanTong University. The concentration of AFP in the serum samples was measured with abbott immunoassay instrument according to the calibrator dose response curve by the chemiluminescence method，and the data were collected. Expression of miRNAs was measured by real-time quantitative reverse transcription PCR. ROC curves and t test were made by SPSS.17.0 to determine the feasibility of using serum miRNA level as diagnostic biomarkers for clinical HCC detecting. Results: Both miR-122 and miR-221 levels were significantly overexpressed in HCC specimens. Areas under receiver operating characteristic was 91.70%（89.2% of sensitivity and 77.8% of specificity）、94.50%（97.29% of sensitivity and 77.78% of specificity）、99.70%（90.90% of sensitivity and 77.80% of specificity) respectively. The accuracy reached 87.27%、90.90%、90.91% respectively. The accuracy of combined AFP with other two indicators(miR-122、miR-221) was the highest of all with 95.40% (Sensitivity: 98.50% and Specificity: 94.0%). According to the correlation analysis, there was no significant correlation between miRNAs and AFP in the serum of HCC. Conclusions: Serum miR-122, miR-221 can serve as potential diagnostic markers for detecting of HCC. The combination of miR-122 and miR-221 boosted the diagnostic performance in HCC detection.