Purpose: Hepatocyte growth factor (HGF) and its receptor Met are involved in the initiation, progression, and metastasis of numerous systemic and central nervous system tumors. Thus, an anti-HGF monoclonal antibody (mAb) capable of blocking the HGF-Met interaction could have broad applicability in cancer therapy. Experimental Design: An anti-HGF mAb L2G7 that blocks binding of HGF to Met was generated by hybridoma technology, and its ability to inhibit the various biological activities of HGF was measured by in vitro assays. The ability of L2G7 to inhibit the growth of tumors was determined by establishing s.c. and intracranial xenografts of human U87 and U118 glioma cell lines in nude mice, and treatment with 100 μg of L2G7 or control given i.p. twice per week. Results: MAb L2G7 strongly inhibited all biological activities of HGF measured in vitro, including cell proliferation, cell scattering, and endothelial tubule formation. Treatment with L2G7 completely inhibited the growth of established s.c. xenografts in nude mice. Moreover, systemic administration of L2G7 from day 5 induced the regression of intracranial U87 xenografts and dramatically prolonged the survival of tumor-bearing mice from a median of 39 to >90 days. L2G7 treatment of large intracranial tumors (average tumor size, 26.7 mm3) from day 18 induced substantial tumor regression (control group, 134.3 mm3; L2G7 treated group, 11.7 mm3) by day 29 and again prolonged animal survival. Conclusions: These findings show that blocking the HGF-Met interaction with systemically given anti-HGF mAb can have profound antitumor effects even within the central nervous system, a site previously believed to be resistant to systemic antibody-based therapeutics. © 2006 American Association for Cancer Research.