Background: Hepatocellular carcinoma (HCC) still represents a medical challenge in cancer therapy. In recent years the introduction of new targeted therapies has radically changed the approach to the disease and patients outcome. Currently the therapeutic stronghold is a TKIs directed against the VEGF family (sorafenib). Polymorphisms of VEGF and its receptor genes are involved in regulating angiogenesis and lymphangiogenesis and thus in growth tumor control. The aim of our study is to evaluate the potential predictive and prognostic role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. Methods: 38 histologic samples (biopsies and surgical specimens) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients time to progression (TTP) and overall survival (OS) were analysed. Results: VEGF-AI rs25648 C>T polymorphism was statistically significant in OS (15.0 months for C vs 9.4 months for T; p=0.025). VEGF-AII rs10434 G>A was statistically significant for TTP (4.1 months for G vs 1.2 months for A; p=0.0076) and OS (14.2 months for G vs 1.7 for A; p<0.0001). VEGF-CII rs7664413 C>T was significant in TTP (13.4 months for C vs 2.0 for T; p=0.0125) and OS (14.7 months for C vs 5.6 for T; p=0.0007). VEGR2-I rs1870377 A>T was significant in TTP (19.9 months for A vs 3.0 for T; p=0.0271) and OS (29.6 months for A vs 11.9 for T; p=0.0096). Conclusions: In our analysis patients with G polymorphism at rs10434, C polymorphism at rs7664413 and A polymorphism at rs1870377 seem to have a better response (PFS and OS) during treatment with sorafenib. Patients with C polymorphism of rs25648 seem to have an advantage only for OS. These polymorphisms of the VEGF-A gene are probably connected with a better control of the neoangiogenesis process during TKIs therapy, maybe leading to vasculature normalization. VEGF-C is a ligand of VEGR2 and seems to have a closely relationship with lymphangiogenesis.