Angiogenesis, the formation of blood vessel, is required for invasive tumor growth and metastasis. In this study, the effects of lidocaine, an amide-link local anesthetic, on angiogenesis and tumor growth were investigated.In vitro angiogenesis assays were conducted using human umbilical vascular endothelial cell (HUVEC). Essential molecules involved in vascular endothelial growth factor (VEGF) signaling were analyzed. Tumor angiogenesis was analyzed using in vivo mouse tumor model.Lidocaine at clinically relevant concentrations inhibited angiogenesis. Lidocaine inhibited endothelial cell in vitro capillary network formation on Matrigel through interfering early stage of angiogenesis. In addition, lidocaine inhibited vascular endothelial growth factor (VEGF)-stimulated endothelial cell migration and proliferation without affecting cell adhesion. Lidocaine also induced endothelial cell apoptosis in the presence of VEGF. Lidocaine suppressed VEGF-activated phosphorylation of VEGF receptor 2 (VEGFR2), PLCγ-PKC-MAPK and FAK-paxillin in endothelial cells, demonstrating that VEGF, PLC, MAPK and FAK-paxillin suppression is associated with the antiangiogenic effect of lidocaine. Importantly, the in vitro observations were translatable to in vivo B16 melanoma mouse model. Lidocaine significantly inhibited tumor angiogenesis, leading to delay of tumor growth.This study is the first to report that lidocaine acts as an angiogenesis inhibitor. The findings provide preclinical evidence into the potential mechanisms by which lidocaine may negatively affect cancer growth and metastasis.