Background: HCC still represents a medical challenge in cancer therapy. The introduction of new 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: 142 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-A rs25648 polymorphism was statistically significant in OS (15.0 mo for C vs 9.4 for T p=0.025). VEGF-A rs10434 was statistically significant for TTP (4.1 mo for G vs 1.2 for A p=0.0076) and OS (14.2 mo for G vs 1.7 for A p<0.0001). VEGF-C rs7664413 was significant in TTP (13.4 mo for C vs 2.0 for T p=0.0125) and OS (14.7 mo for C vs 5.6 for T p=0.0007). VEGFR2 rs1870377 was significant in TTP (19.9 mo for A vs 3.0 for T p=0.0271) and OS (29.6 mo for A vs 11.9 for T p=0.0096). At multivariate analysis VEGF-C rs7664413 has been confirmed as an independent factor for TTP (HR=0,61) and OS (HR=0,65). Conclusions: In our analysis patients with G polymorphism at rs10434, C polymorphism at rs7664413 and A polymorphism at rs1870377 have a better response (PFS and OS) during treatment with sorafenib. Patients with C polymorphism of rs7664413 and A polymorphism of rs1870377 show a favourable impact in this setting. Notably, VEGFR polymorphism result closely related to the treatment response and the specific signalling of sorafenib. Thus analysis of VEGF and its receptor genes polymorphisms represents a clinical tool to identify patients with favourable response to sorafenib presumably related to a more efficient control of tumor growth.