Several studies have reported reduced miR-199a-3p expression in hepatocellular carcinoma (HCC). In an effort to discover important target genes for miR-199a-3p that may be related to HCC development or progression, we identified the tetraspanin, transmembrane glycoprotein CD151. Luciferase reporter assays and western blotting identified CD151 as a bona fide miR-199a-3p target gene. While CD151 protein was increased in the mesenchymal but not the epithelial HCC cell lines, CD151 knockdown with siRNA did not reduce HCC cell proliferation in either group of cells. miR-199a-3p reduced in vitro invasion and migration of CD151-positive HCC cells. Examination of the mRNA and protein expression in pairs of primary HCC tumors and adjacent benign tissues showed that not only was CD151 mRNA and protein increased in the tumors but also that an inverse correlation exists between the miR-199a-3p and CD151 RNA expression. We report that CD151 is a target of miR-199a-3p and that increased CD151 protein resulting from reduced miR-199a-3p could contribute to the development of metastatic HCC.