Objective To investigate the effect of serpin E2 on the proliferation, invasion and migaration of colon cancer cells. Methods The expression of serpin E2 was detected by immunohistochemistry in 30 pairs of colon cancer and adjacent tissues. The expression of serpin E2 in colon cancer SW480 cells was down-regulated by siRNA. The down-regulation effect was verified by real-time fluorescent quantitative PCR and Western blot analysis. CCK-8 assay and plate cloning assay were used to detect the proliferation of colon cancer cells. TranswellTM assay was performed to detect the changes in cell invasion and migration. Results Serpin E2 was obviously overexpressed in the colon cancer tissue. The proliferation, invasion and migration ability of SW480 cells were inhibited significantly after the down-regulation of serpin E2 expression. Conclusion Knockdown of serpin E2 might inhibit the proliferation, invasion and migration of SW480 cells.