MicroRNA-122a (miR-122a) is a liver-specific miRNA that is frequently downregulated in hepatocellular carcinoma (HCC). The exact functional role of miR-122a and its target in HCC remain largely unknown. We developed a lentiviral vector for the expression of pre-miR-122a (Lenti-miR-122a). Lenti-miR-122a inhibited HCC cell growth and induced apoptosis in vitro. We employed proteomic profiling to identify the target proteins of miR-122a. In total, ten proteins with differential expression in HCC cells infected with Lenti-miR-122a were identified. Amongst them, downregulation of peroxiredoxin 2 (PRDXII) by miR-122a was validated by Western blotting. Using bioinformatics analysis, predictable target sites of miR-122a were identified in the 5'-UTR of PRDXII mRNA. Luciferase reporter assay confirmed the regulation of miR-122a on 5'-UTR of PRDXII. In conclusion, PRDXII was identified to be the new target of miR-122a.