Abstract Objectives We investigated the effects of xeroderma pigmentosum D (XPD) on the growth of hepatoma cells and the expressions of P21, Bax, Bcl-2 and Hepatitis B virus X protein (HBx). In addition, we examined whether XPD affected the aforementioned genes via the P53 pathway. Methods Human hepatoma cells (HepG2.2.15) were transfected with XPD expression vector, followed by incubation with Pifithrin-α (P53 inhibitor). By using RT-PCR and Western blotting, the expression levels of XPD, P53, phospho-P53 (ser-15), P21, Bax, Bcl-2 and HBx were detected. The cell cycle and the apoptosis rate were examined with flow cytometry, and the cell viability was detected by MTT. Results Over-expression of XPD up-regulated the expressions of P53, phospho-P53 (ser-15), P21 and Bax but down-regulated the expressions of Bcl-2 and HBx. XPD inhibited the viability of HepG2.2.15 and exacerbated the apoptosis. However, the inhibition of P53 by Pifithrin-α abolished the above-mentioned effects of XPD. Conclusion XPD could suppress growth of hepatoma cells, up-regulate the expressions of P21 and Bax, and down-regulate the expressions of Bcl-2 and HBx through the P53 pathway. There may be mutual influences among XPD, P53 and HBx that co-regulate hepatocarcinogenesis.