Objective：To investigate the effect of epidermal growth factor receptor（EGFR） expression on the proliferation，invasion and migration of malignant peripheral nerve sheath tumors（MPNST） cells，and its regulation mechanism on C-X-C motif chemokine receptor 4/C-X-C motif chemokine ligand 12（CXCR4/CXCL12） signaling pathway. Methods：The tumor tissues of 50 cases of MPNST who were surgically removed from the lesions in our hospital from June 2017 to June 2019 were collected as the observation group，and 50 cases of dermal neurofibroma（DNF） were collected as the control group. Immunohistochemistry was used to detect the expression of EGFR. Cell experiments were divided into 3 groups：Normal group（cells were regularly cultured without external intervention）；Control group（cells were transfected with 150 nmol/L EGFR-siRNA-NC and then regularly cultured）；exper－imental group（EGFR-siRNA group，cells were transfected with 150 nmol/L EGFR-siRNA and then regularly cultured）. Besides，5-ethynyl-2’-deoxyuridine（EdU） assay was used to detect the proliferation ability of each group of cells；the Transwell chamber test was used to detect the migration and invasion ability of each group of cells；the nude mouse subcutaneous tumor model was used to detect the growth and migration ability in vivo of each group of cells；gene chips and real-time quantitative polymerase chain reaction（RT-qPCR） was used to determine the target genes of the silence of EGFR；Western blot was used to detect the expression levels of EGFR，CXCR4 and CXCL12 in each group of cells. Results：The immunohistochemical results showed that compared with the control group’s（2.35±0.32）%，the positive expression rate of EGFR in the tumor tissues of MPNST patients was （78.94±12.25）%，with significant differences（t=123.573，P=0.000）. Compared with the Normal group，the cell proliferation（t=53.147，P=0.000），invasion and migration ability（t=26.947，t=34.638，both P=0.000），the growth and migration ability in vivo（t=15.683，t=22.197，both P=0.000） of the EGFR-siRNA group were significantly reduced. Gene chip and RT-qPCR analysis confirmed that CXCR4 and CXCL12 were the target genes of EGFR. Compared with the Normal group，the expression of EGFR，CXCR4 and CXCL12 in the cells of the EGFR-siRNA group were decreased significantly（t=2.579，t=2.673，t=2.945，all P=0.000）. Conclusion：In MPNST，EGFR can regulate the expression of CXCR4/CXCL12 signaling pathway and regulate the biological malignant behavior of tumors. Silencing the expression of EGFR can significantly reduce the proliferation，invasion and migration of cancer cells.