Down‐regulation of microRNA‐26a (miR‐26a) is associated with poor prognosis of hepatocellular carcinoma (HCC), but its functional mechanism in HCC remains unclear. In this study, we investigated the roles of miR‐26a in tumor growth and metastasis of HCC and found that miR‐26a was frequently down‐regulated in HCC tissues. Down‐regulation of miR‐26a correlated with HCC recurrence and metastasis. Through gain‐ and loss‐of‐function studies, miR‐26a was demonstrated to significantly inhibit in vitro cell proliferation, migration, and invasion. In addition, miR‐26a induced G1 arrest and promoted apoptosis of HCC cells. Importantly, miR‐26a suppressed in vivo tumor growth and metastasis in nude mice models bearing human HCC. Interleukin‐6 (IL‐6) was identified as a target of miR‐26a. Knockdown of IL‐6 induced effects on HCC cells similar to those induced by miR‐26a. In contrast, IL‐6 treatment abrogated the effects induced by miR‐26a up‐regulation. Moreover, miR‐26a dramatically suppressed expression of signal transducer and activator of transcription 3 (Stat3) target genes, including Bcl‐2, Mcl‐1, cyclin D1, and MMP2. IL‐6 treatment antagonized this effect, while knockdown of IL‐6 by IL‐6 short hairpin RNA (shIL‐6) induced inhibitory effects on the expression of p‐Stat3 and its main target genes, similar to miR‐26a. The messenger RNA and protein levels of IL‐6 inversely correlated with miR‐26a in HCCs. Patients with high miR‐26a or low IL‐6 in HCC tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR‐26a, IL‐6, and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. Conclusion: miR‐26a could suppress tumor growth and metastasis of HCC through IL‐6‐Stat3 signaling and is a novel prognostic marker and therapeutic target for HCC. (HEPATOLOGY 2013)