Ganoderma lucidum Polysaccharide Peptide (Gl-PP) has shown some effects as anti-tumors in mice and potential anti-angiogenesis. In this study, we elucidated the possible mechanism of Gl-PP action on anti-angiogenesis of tumor. Our research indicated that the proliferation of HUVECs was inhibited by Gl-PP in a dose-dependent fashion, but not because of cytotoxicity. Flow cytometric studies revealed that Gl-PP treatment of HUVECs could induce cell apoptosis directly. Moreover, addition of Gl-PP also led to a reduction of Bcl-2 anti-apoptotic protein expression and an increase of Bax pro-apoptotic protein expression of HUVECs. Therefore, inducing cell apoptosis by Gl-PP might be the mechanism of inhibiting HUVEC proliferation. Human lung carcinoma cells PG when exposed to high dose of Gl-PP in hypoxia for 18 h resulted in a decrease in the secreted VEGF. Taken together, these findings support the hypothesis that the key attribute of the anti-angiogenic potential of Gl-PP is that it may directly inhibit vascular endothelial cell proliferation or indirectly decrease growth factor expression of tumor cells.