OBJECTIVE To explore the efficacy of small/short interfering RNA- insulin-like growth factor 1 receptor(siRNA-IGF1R) in the treatment of sorafenib-resistant liver cancer. METHODS SiRNA-IGF1R was transfected into sorafenib-resistant hepatocellular carcinoma cells, and the effects of blank control, siRNA-NC(Lipo3000), siRNA-IGF1R, sorafenib, siRNA-IGF1R combined with sorafenib on the proliferation, migration and invasion of the drug-resistant cells were compared by CellTiter-Glo^® luminescent cell viability assay(CTG) detection and Transwell assay. In vivo, the mouse xenograft tumor model was constructed by drug-resistant cell line, and the tumor volume, mouse body weight, and IGF1R expression in blank control, siRNA-IGF1R, sorafenib, siRNA-IGF1R combined with sorafenib groups were compared. RESULTS In vitro, compared with the blank control group, siRNA-NC(Lipo3000) and sorafenib alone had no effect on the proliferation, migration and invasion of sorafenib-resistant HepG2 cells. SiRNA-IGF1R and siRNA-IGF1R combined with sorafenib treatment inhibited the proliferation, migration and invasion of HepG2-so cells; and the combined effect of the two drugs was superior to that of siRNA-IGF1R treatment alone. In vivo, the combination of siRNA-IGF1R and sorafenib significantly inhibited tumor growth in mice, outperforming the effect of siRNA-IGF1R alone, with no significant difference in mouse body weight; siRNA-IGF1R markedly reduced IGF1R expression in tumor tissues. CONCLUSION IGF1R is a target for the treatment of sorafenib resistance in liver cancer, and siRNA-IGF1R enhances the efficacy of sorafenib in the treatment of drug-resistant liver cancer by knocking down IGF1R.