Background: The introduction of sorafenib for the treatment of advanced HCC radically changed patients’ clinical outcome. However response to treatment as well as toxicity are still largely unpredictable in the single patient. We previously reported that VEGF and VEGFR polymorphisms may have a predictive and prognostic role in this setting, but little is known about the possible correlation with toxicity. The aim of our study was to evaluate whether VEGF and VEGFR genotyping was able to correlate with toxicity in HCC patients receiving sorafenib. Methods: 73 histological samples 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), overall survival (OS) and toxicities were analysed. Results: VEGF-A rs833061 T>C, rs699947 C>A and rs2010963 C>G polymorphisms were statistically significant associated with any grade global (respectively: p=0.031; p=0.018; p=0.003) and cutaneous toxicities (respectively: p=0.043; p=0.019; p=0.025). Furthermore patients with any grade global and cutaneous toxicities showed a better progression free survival and overall survival (global toxicity PFS: 7.0 vs 5.0 months, p=0.016; OS: 26.8 vs 13.0 months, p=0.023) (cutaneous toxicity PFS: 7.6 vs 5.1 months, p=0.033; OS: 22.7 vs 13.3 months, p=0.014) Conclusions: In our analysis patients with polymorphism T at rs833061, C at rs699947 and C at rs2010963 showed a higher rate of toxicities and, accordingly to our previous report, this correlates with a better PFS and OS. 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 tumour growth. The occurrence of toxicity could be an interesting clinical surrogate during sorafenib treatment and may help clinicians in a more cautious and aware management of HCC patients.