The tissue factor-factor VIIa (TF/VIIa) complex is believed to activate protease-activated receptor-2 (PAR2) and to trigger the malignant behavior of various types of cancer cells. In our previous study, it was demonstrated that TF and PAR2 were overexpressed in high metastatic potential colon cancer cells (SW620). Both PAR2 agonist (SLIGKV-NH2, PAR2-AP) and factor VIIa facilitated SW620 cell proliferation and migration. In the present study, the molecular mechanisms of TF/VIIa-induced SW620 cell proliferation and migration were investigated. It was found that factor VIIa (10 nM) significantly increased interleukin-8 (IL-8) expression at the mRNA and protein levels, enhanced TF mRNA expression and TF activity, and decreased caspase-7 expression at the mRNA and protein levels in the SW620 cells. These effects of factor VIIa were similar to those of PAR2-AP. All effects of factor VIIa were blocked by anti-TF and anti-PAR2 antibodies, but not by an isotype control antibody. Furthermore, both PAR2-AP and factor VIIa decreased the phosphorylation of p38 mitogen-activated protein kinase (MAPK). The results of this study suggest that the TF/VIIa complex regulates IL-8, TF and caspase-7 expression in SW620 cells via PAR2 activation, thereby promoting colon cancer cell proliferation and migration. The p38MAPK signal transduction pathway may negatively regulate these processes.