Taken together, our results showed that sorafenib administration up‐regulated SESN2 expression in both Bel‐7404 and SNU‐368 HCC cell lines and the knockdown of SESN2 not only reduced HCC cell viability but also promoted apoptosis of the HCC cells, demonstrating that SESN2 up‐regulation contributed to sorafenib primary resistance in HCC. The gene discussed is SESN2; the disease is hepatocellular carcinoma.