Objective: To investigate the miR-376c expression in hepatocellular carcinoma (HCC) and its clinical significance and action mechanism. Methods: The miR-376c expressions in HCC tissues and tumor adjacent tissues as well as in different HCC cell lines and normal hepatic cells were determined by real-time PCR, and the relations of miR-376c expression with the clinicopathologic features and prognosis of HCC patients were analyzed. After the HCC cells were transfected with miR-376c mimics or negative control sequence, the cell migration and invasion were measured by Transwell assay and wound healing assay respectively, and the protein expression of high mobility group A2 (HMGA2), a potential downstream target of miR-376c, was measured by Western blot analysis. The protein expressions of HMGA2 in HCC tissues were also examined by immunohistochemical staining, and then the correlation between miR-376c and HMGA2 expressions was analyzed. Results: Compared with tumor adjacent tissues or normal hepatic cells, the miR-376c expressions in HCC tissue and different types of HCC cells were significantly down-regulated (all P<0.05); the miR-376c expression was significantly related with the portal vein infiltration (P=0.019), advanced TNM stage (P=0.012) and advanced Edmondson degree (P=0.009); the 3-year survival rate in patients with low miR-376c expression was significantly lower than that in those with high miR-376c expression (P=0.0081). In HCC cells compared with HCC cells transfected with negative control sequence, the numbers of migrating and invading cells (56.00 vs. 26.00; 45.33 vs. 18.33) and wound healing rate (95.3% vs. 60%) were significantly reduced, and the HMGA2 protein expression was significantly down-regulated (all P<0.05); the HMGA2 protein expression in HCC tissues with high miR-376c expression was significantly lower than that in those with low miR-376c expression (P<0.05), and the miR-376c expression was negatively correlated with HMGA2 expression in HCC tissues (r=–0.541, P<0.01). Conclusion: MiR-376c is probably a tumor suppressor, and is down-regulated in HCC, which thereby weakens the inhibition on HMGA2 and promotes the migration and invasion of HCC cells.