Abstract: Objective: To study the effect and mechanism of EGFR signaling pathway on prolifer-ation, adhesion and invasion of A375 cells. Methods: High EGFR expression of A375 cells of human melanoma was found and cultured by diluted clone assay and cell culture technique. The cell growth was analyzed using MTT assay. The cell adhesion and invasion to ECM were measured by MTT and Boyden chamber method. Expression levels of P-EGFR and P-AKT proteins were determined using Western blot. Expression levels of MMP-2, MMP-9, TIMP-1 and of TIMP-2 mRNA were determined by RT- PCR. Results: Exogenous EGF could up-regulate P-EGFR and P-AKT at 24h, but had no fur-ther effect on the growth and proliferation of A375 cells until 72h. Meanwhile significant enhancement of adhesion and invasion to ECM was observed at 24h of EGF addition in contrast to the control (P<0.05). AG1478 (20μmol/L) or LY290042 (10μmol/L) could abrogate EGF effects. They could inhibit the growth and proliferation of A375 cells in a time-dependent manner (P<0.01) and reduce the cell adhe-sion and cells through Matrigel (P<0.01). EGF increased the levels of mRNA of MMP- 2 and MMP-9and reduced the levels of mRNA of TIMP-1 and TIMP-2. AG1478 could reduce the levels of mRNA of MMP-2 and MMP-9 and increased the levels of mRNA of TIMP-1, but TIMP-2 was not changed, sothat ratios of MMP-2/TIMP-2 mRNA and MMP-9/TIMP-1 mRNA were significantly reduced. Conclu-sions: EGFR-PI3K signaling pathway mediates invasion and metastasis of human melanoma. The ratiosof MMP-2/TIMP-2 mRNA and MMP-9/TIMP-1 mRNA might be playing important roles in promotingor inhibiting metastasis of human melanoma.