MicroRNAs (miRNAs) are small non-coding RNAs, 18-25 nucleotides long and have an important role in post-transcriptional regulation of gene. Several aspects of cellular activities such as cell growth, proliferation and differentiation are regulated by miRNAs. In many cancers and malignancies, up- or downregulation of different miRNAs has been reported. In human hepatocellular carcinoma (HCC), upregulation of miR-21 has been reported in human in vitro studies. Here, we made an assessment of the effect of miR-21 degradation on viability and apoptosis of HCC cell line (HepG2) using locked nucleic acid (LNA). At different time points (24, 48, 72 h) after LNA-anti-miR-21 transfection, 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide assay and Annexin/propidium iodide staining were performed. The results show that miR-21 degradation can decrease the viability of cells, mainly by induction of apoptosis and necrosis. These findings suggest that degradation of miR-21 could be used as a novel approach in treatment of HCC.