Cisplatin is a widely used anticancer drug; however, resistance to cisplatin-based chemotherapy is a major cause of treatment failure in patients with tumors. The present study was undertaken to investigate whether and how endoplasmic reticulum (ER) stress initiated by tunicamycin, which inhibits glycosylation, influences cisplatin-induced apoptosis in HepG2 cells. Pretreatment of HepG2 cells with ER stress inducers brought about a decrease in both cisplatin-induced cytotoxic effects and apoptosis. In order to further explore the mechanism underlying tumor resistance to cisplatin, we observed that increased nuclear export of endogenous p53 protein by pharmacological inducers of ER stress, such as tunicamycin, was associated with the suppression of cisplatin-induced apoptosis. These results suggested that tumor suppressor p53 protein may play a key role in cisplatin-induced HepG2 cells apoptosis. It is therefore suggested that the treatment of some tumor patients with cisplatin be combined with the down-regulation of endogenous ER stress to improve the clinical results of cisplatin-based chemotherapy.