ADAMTS5 is a member of the A Disintegrin-like And Metalloproteinase with ThromboSpondin motifs (ADAMTS) family of secreted metalloproteinases with multiple proteoglycan substrates. Although well characterized for its role in cartilage degradation and arthritis, how it influences cancer remains unclear. We have previously shown that the first thrombospondin type 1 repeat (TSR1, the central TSR) but not TSR2 (the C-terminal TSR) of ADAMTS5 is anti-angiogenic in vitro. Coupled with previous reports that ADAMTS5 expression is altered in several human cancers, we hypothesized that this proteoglycanase may play an important role in cancer and angiogenesis. Here, we demonstrated that overexpression of full-length ADAMTS5 suppressed B16 melanoma growth in mice. The reduced tumor growth is correlated with diminished tumor angiogenesis, together with reduced tumor cell proliferation and increased tumor cell apoptosis. Catalytically active ADAMTS5 proteolytic fragment also suppressed angiogenesis in vitro. The catalytic activity of ADAMTS5 is dispensable for its anti-tumorigenic function, as the full-length active site mutant E411A presented similar tumor suppression activity. Domain mapping and mechanistic studies revealed that ADAMTS5 inhibits B16 tumorigenesis through its TSR1 by suppressing tumor angiogenesis, likely by down-regulating pro-angiogenic factors such as vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), and platelet-derived endothelial growth factor (PD-ECGF) in the tumor milieu. This is the first report that ADAMTS5 is an anti-angiogenic and anti-tumorigenic protein independent of its proteoglycanase activity.