In summary, our study revealed that the EGFR/HER2 inhibitors gefitinib and lapatinib, in combination with the IGF-1R inhibitor linsitinib, have synergistic effects on the inhibition of proliferation, the cell cycle arrest, the apoptosis, the invasion, and the migration of ESCC cells in vitro, as well as on tumor growth in vivo. This evidence concerns the gene EGFR and esophageal squamous cell carcinoma.