〔Abstract〕 Objective To investigate the effects of 4-phenylbutyric acid(4-PBA) inhibiting the endoplasmic reticulum stress(ERS) of hepatoma cells on the antitumor effect of Huaierqing cream. Methods The hepatoma cells were treated with 0(as control), 2, 4, 6 and 8 mg/ml of Huaier extract for 24 h. Then the viability of the cells was determined by MTT. The apoptosis rate of the cells was determined by flow cytometry.The expression levels of the anti-apoptotic proteins Bcl2 and Bax, and the ERS-related proteins GRP78, PERK and IRE1 were determined by Western blot. Then the cells were divided into 4 groups: control group, 4-PBA group, Huaier group, and 4-PBA+Huaier group. After treated accordingly for 24 h, they were determined expression of ERS-related proteins PERK and IRE1, cell viability, apoptosis rate, and expression of Bcl-2 and Bax. Results Compared with the Huaier group, the cells in the 4-PBA+Huaier groups showed significantly lower viability. Apoptosis rates of the HepG2 and Hep3 B cells in the 4-PBA+Huaier group were(1.12±16.98)% and(2.32±15.68)% respectively, while those of the Huaier group were(1.15±12.89)% and(2.58±10.67)% respectively, and the difference was statistically significant(P<0.05). Conclusion The combination of Huaierqing cream and 4-PBA can inhibit the occurrence of ERS in hepatoma cells, inhibit the viability and increase the apoptosis, so as to enhance the antitumor effect of Huaierqing cream.