Previous studies demonstrated that CD147 molecule, highly expressed on the surface of various malignant tumor cells, significantly correlated with the malignancy of these cancers; however, the role of HAb18G/CD147 in endothelial cells has yet to be established. In this study, we found that the expression of HAb18G/CD147 was significantly upregulated in activated HUVECs. The inhibition of HAb18G/CD147 expression by specific siRNA led to significantly decreased angiogenesis in vitro. Our data indicate that HAb18G/CD147 may regulate angiogenesis via several mechanisms including proliferation, survival, migration, MMPs secretion, and PI3K/Akt activation. Our findings for the first time suggest that upregulation of HAb18G/CD147 in activated HUVECs might play an important role in angiogenesis.