PURPOSE: To investigate whether tissue factor (TF) regulates fibroblast growth factor (FGF)-2-induced angiogenesis in retinoblastoma. METHODS: In an orthotopic transplantation mouse model of retinoblastoma, immunofluorescence staining for TF and CD31 (an endothelial cell maker) was performed. With treatment of FGF-2 (10 ng/ml), TF expression in human umbilical vein endothelial cells (HUVECs) was measured by Western blotting. To confirm the role of TF in tumor angiogenesis in retinoblastoma, anti-angiogenic activity of TF pathway inhibitor (TFPI) was investigated by treating TFPI on FGF-2-induced proliferation, migration and in vitro tube formation of HUVECs. In addition, inhibition of ERK1/2 phosphorylation by TFPI was measured by Western blot analysis. RESULTS: TF was highly expressed on vascular endothelial cells of retinoblastoma, co-localized with CD31. With FGF-2-induced proliferation of HUVECs, TF expression was significantly up-regulated. Interestingly, TFPI effectively inhibited FGF-2-induced proliferation, migration and in vitro tube formation of HUVECs, which was accompanied by inhibition of ERK1/2 phosphorylation. CONCLUSIONS: TF is involved in tumor angiogenesis of retinoblastoma via extracellular signal-regulated kinase pathway.