Abstract: OBJECTIVE To investigate the effect and related mechanism of Huaier granule on Sorafenib-resistant hepatocellular carcinoma cells BEL-7402/S. METHODS The proliferation-toxicity effect of Huaier granule on BEL-7402/S cells and the reversal multiple of drug resistance to Sorafenib were measured by CCK-8 assays. The effects of Huaier granule on the mRNA and protein levels of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in BEL-7402/S cells were detected by qPCR and Western blot， respectively. RESULTS Huaier granule inhibited the activities of BEL-7402/S cells， and partially reversed the resistance of BEL-7402/S cells to Sorafenib at the dose of no significant cytotoxicity， and the reversal multiple of drug resistance was 2.08; the results of qPCR showed that Huaier granule may down-regulate the mRNA level of HIF-1α in BEL-7402/S cells， but had no significant effect on the mRNA level of VEGF. The results of Western blot showed that Huaier granule may down-regulate the protein levels of HIF-1α and VEGF in BEL-7402/S cells. CONCLUSION Huaier granule may partially reverse the drug resistance of BEL-7402/S cells to Sorafenib， and its mechanism may be related to the decrease of the expression of HIF-1α and VEGF.