The hepatitis B virus (HBV)-encoded X antigen (HBxAg) may contribute to the development of epatocellular carcinoma (HCC) through the upregulated expression of selected cellular genes. To identify these genes, RNAs isolated from HBxAg-positive and -negative HepG2 cells were compared by PCR select cDNA subtraction. One gene overexpressed in HBxAg-positive cells by Northern and Western blotting is the ribosomal protein S15a. The S15a mRNA is 535 base pairs, encoding a protein 130 amino acids long with a molecular weight of 14.3kDa. S15a expression was upregulated in HBV-infected livers, where it costained with HBxAg. Overexpression of S15a stimulated cell growth, colony formation in soft agar, and tumor formation in SCID mice. Hence, HBxAg upregulated the expression of S15a, the latter of which participates in the development of HCC, perhaps by altering the integrity of translation.