Background: Tumour cells adapt to hypoxic microenvironment via the activation of numerous molecules, among which hypoxia inducible factor 1 (HIF-1) is the most important. HIF-1 plays a crucial role in tumour angiogenesis triggering the transcription of several genes including the vascular endothelial growth factor (VEGF). Currently the therapeutic stronghold of advanced hepatocellular carcinoma (HCC) is the antiangiogenetic TKIs sorafenib. The overexpression of HIF-1 in HCC is associated with tumour angiogenesis, invasion, metastasis, treatment resistance and poor prognosis. In our previous report polymorphisms (SNPs) CC+CG>GG of rs2010963 and TT+CT>CC rs4604006 of VEGF have been shown to predict clinical outcome in HCC patients treated with sorafenib. Methods: From a large database a preliminary analysis on 90 HCC patients receiving sorafenib was conducted to assess the role of HIF-1 SNPs in determining the clinical outcome in this setting. Tumour histologic samples were tested for 8 different HIF-1 SNPs. Patients progression free survival (PFS) and overall survival (OS) were analysed. Results: At univariate analysis CC>AA+AC of rs1951795, TT>CC+CT of rs10873142, AA+AG>GG of rs12434438 SNPs were statistically significant for PFS and OS. At multivariate analysis rs1951795 of HIF-1, rs2010963 of VEGF-A and rs4604006 of VEGF-C have been confirmed as independent factors (Table). Conclusions: This investigation on HIF-1 SNPs, following our previous discoveries on VEGF and its receptors, may represent a clinical tool to identify patients with favourable response to sorafenib, presumably related to a more efficient control of tumour growth.