Background: Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer worldwide and the second most frequent cause of cancer death. The aim of this study is to investigate the early diagnostic value of a panel of peripheral blood exosomal micro-RNAs (miRNAs) in patients with HCC compared with patients with Hepatitis B virus (HBV) and hepatocirrhosis. Patients and methods: Blood samples from 72 patients with HCC, 72 patients with hepatocirrhosis and 72 patients with HBV were obtained at Beijing Friendship Hospital, Capital Medical University. The miRNA expression levels were detected by real-time polymerase chain reaction (RT-PCR). Areas under curve (AUCs) were used to compare diagnostic values of plasmic and exosomal miRNAs. Results: We screened plasmic and exosomal solutions of 3 HCC, 3 cirrhosis and 3 HBV patients to perform miRNA microarray analysis. Three distinctly differential microRNAs including miRNA-26a, miRNA-29c, and miRNA-21 were selected to perform further evaluation. First, we found that the expressions of miRNA-26a, miRNA-29c, and miRNA-21 were significantly lower in patients with HCC compared with cirrhotic and HBV group in both exosomes and plasma. Second, we found miRNA-26a, miRNA-29c, and miRNA-21 were significantly down-regulated in HCC tumor tissues compared with normal tissues. Thirdly, we found miRNAs in exosomes had better diagnostic value for patients with HCC compared with plasmic miRNAs among different groups. Conclusions: In conclusion, we found that the expression of miRNA-26a, miRNA-29c, and miRNA-21 were significantly lower in patients with HCC, and we confirmed miRNA-26a, miRNA-29c, and miRNA-21 could be identified as independent diagnostic biomarkers for patients with HCC.