Matriptase/MT-SP1, a type II membrane serine protease widely expressed in normal epithelial cells and human carcinoma cells, is thought to be involved in cancer progression. To clarify this possibility, we overexpressed exogenous matriptase in the human stomach cancer cell line AZ521. In vitro, the matriptase transfectant (Mat-AZ521) and the control transfectant (Mock-AZ521) showed a similar growth rate, although the saturation cell density was significantly higher with the Mat-AZ521. When implanted into nude mice subcutaneously or intraperitoneally, Mat-AZ521 cells grew faster and produced much larger solid tumors than Mock-AZ521 cells. The overexpression of matriptase in AZ521 cells shortened the survival time of tumor-bearing mice. Histological analysis showed that both the number and the size of blood vessels in tumor tissues were significantly higher in the Mat-AZ521 tumors than the Mock-AZ521 ones. Moreover, it was found that purified matriptase activated one of the important matrix metalloproteinases, stromelysin (MMP-3). These results suggest the possibility that the matriptase-dependent activation of MMP-3, as well as the direct activity of matriptase, promotes tumor growth and angiogenesis by enhancing extracellular matrix degradation in tumor cell microenvironments.