Background: Metastatic renal cell carcinoma (mRCC) 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 strongholds are TKIs directed against the VEGF family. 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 mRCC patients receiving first-line sunitinib. Methods: 41 histologic samples (biopsies and surgical specimens) of mRCC patients were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients progression free survival (PFS) and overall survival (OS) were analyzed for first line treatment. Results: VEGF AIV rs833061 C>T polymorphism was statistically significant in PFS (17 months for C vs 4 months for T; P = 0.0029) and OS (35.93 months for C vs 11 months for T; P = 0.0267). VEGF AV rs699947 A>C was statistically significant for PFS (17 months for A vs 3.97 months for C; P = 0.0023) and OS (35.93 months for A vs 10.98 for C; P = 0.0272). VEGF AVI rs2010963 G>C was significant in PFS (16.98 months for G vs 4.65 for G/C vs 2.73 for C; P = 0.0188). VEGR3 III rs6877011 C>G was significant in PFS (8.22 months for C vs 2.22 for C/G; P = 0.0361) and OS (35.93 months for C vs 12.08 for C/G; P = 0.0183). Conclusions: In our analysis patients with C polymorphism of rc833061, A polymorphism rs699947 and G polymorphism of rs2010963 seem to have a better PFS and OS in first line. 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. Patients with C polymorphism of rs6877011 seem equally to have a favourable impact in first line therapy. VEGFR-3 role is still matter of debate but seems to be involved in vessels sprouting and architecture.