The constitutive over-expression of the retinol dehydrogenase 10 (RDH10) gene, involved in retinoic acid (RA) biosynthesis, produced in HepG2 cells a significant antiproliferative response, but not signs of apoptosis. An indirect assay based on the Chloramphenicol AcetylTransferase (CAT) reporter gene driven by a retinoic acid responsive element (RARE) suggests in genetically modified HepG2 cells an increase of the endogenous RA concentration. Furthermore, the growth arrest of HepG2 cells over-expressing the RDH10 gene was associated with the upregulation and downregulation of, respectively, RARbeta/p21(Cip1) and CycE/CdK2 mRNAs. These results indicated that forced expression of RDH10 produces antiproliferative effects highly comparable to those achieved by retinoids treatment and thus the development of a gene therapy, finalized at the restoration of the enzymatic and receptorial machinery of the RA pathway, could be a possible curative strategy for hepatocellular carcinoma (HCC).