SY0916 is a novel platelet-activating factor receptor antagonist. The objective of this study is to explore the anti-angiogenesis effects of SY0916 on human umbilical vascular endothelial cell (HUVEC) and to understand its possible mechanism. The effect of SY0916 on proliferation of HUVEC was measured by the MTT method, whereas the effect of SY0916 on HUVEC chemotaxis was carried out by Boyden chamber assay. The activities of metalloproteinase (MMP)-9 and MMP-2 were detected using gelatin zymography, and the expression of intercellular adhesion molecules-1 (ICAM-1) was measured by Western blot analysis. The 2D tube formation experiment of HUVEC with 10% fetal calf serum on Matrigel was also evaluated. It was shown that SY0916 had significant inhibitory effects on the proliferation and the chemotaxis of HUVEC induced by phorbol-12-myristate-13-acetate in a positive dose-dependent manner. Furthermore, SY0916 could significantly suppress the activity of MMP-2 and MMP-9 and decrease the expression of ICAM-1 in HUVEC. In 2D tube formation test, SY0916 could effectively inhibit the formation of vascular structure on Matrigel. The results showed that SY0916 could block the chemotaxis of HUVEC, and then inhibit the tube formation on Matrigel. Such anti-angiogenesis effect of SY0916 on HUVEC might relate to downregulate the expressions of MMP-2, MMP-9, and ICAM-1.