Hepatocyte growth factor/scatter factor (HGF/SF) contributes to the malignant progression of human gliomas. We investigated the effect of HGF/SF on matrix metalloproteinase‐2 (MMP‐2), membrane type 1 matrix metalloproteinase (MT1‐MMP) and tissue inhibitors of metalloproteinases (TIMPs), expressions of c‐Met/HGF receptor‐positive human glioblastoma cells. Treatment of U251 human glioblastoma cells with HGF/SF resulted in enhanced secretion of MMP‐2 with an increased level of the active form. This was accompanied by enhanced expression (2.5‐fold) of mRNA specific for MMP‐2. The stimulatory effect of HGF/SF on MMP‐2 expression did not occur in the presence of herbimycin A, a protein tyrosine kinase inhibitor. MT1‐MMP, a cell‐surface activator of proMMP‐2, was also up‐regulated by HGF/SF in a dose‐dependent manner. By contrast, the level of TIMP‐1 mRNAs was not altered significantly and that of TIMP‐2 was reduced mildly by the HGF/SF treatment, suggesting that HGF/SF may eventually modulate a balance between MMP‐2 and TIMPs in favor of the proteinase activity in the glioma cell microenvironment. HGF/SF also stimulated MMP‐2 expression of other glioblastoma cell lines. Since glioblastomas frequently co‐express HGF/SF and its receptor, our results suggest that HGF/SF might contribute to the invasiveness of glioblastoma cells through autocrine induction of MMP‐2 expression and activation. Int. J. Cancer 82:274–281, 1999. © 1999 Wiley‐Liss, Inc.