Background: HIF-1α plays a crucial role in tumour angiogenesis triggering the transcription of several genes including VEGF. The overexpression of HIF-1α in HCC is associated with tumour angiogenesis, invasion, metastasis, treatment resistance and poor prognosis. The therapeutic stronghold of advanced HCC is the TKI sorafenib. In our previous report (ALICE-1 study) SNPs rs2010963 and rs4604006 of VEGF have been shown to predict clinical outcome in HCC patients treated with sorafenib. Methods: 210 patients from a multicentre database were eligible for our analysis. Tumour samples were tested for 8 HIF-1α SNPs. Patients PFS and OS were analysed. Results: At univariate analysis CC > AA+AC of rs1951795, TT > CC+CT of rs10873142, AA+AG > GG of rs12434438 SNPs of HIF-1α were statistically significant for PFS and OS. The extended analysis of VEGF and VEGFR SNPs confirms the results of ALICE-1 study. At multivariate analysis rs12434438 of HIF-1α, rs2010963 of VEGF-A and rs4604006 of VEGF-C have been confirmed as independent factors. At the combined analysis of significant SNPs the presence of 2 favourable alleles of rs2010963 and rs4604006 of VEGF compared to only 1 or to none favourable alleles, identifies three populations with different PFS (respectively: 10.8 vs. 5.6 vs. 3.7 months, p < 0,0001) and OS (respectively: 19.0 vs. 13.5 vs. 7.5 months; p < 0,0001). Furthermore the presence of GG genotype of rs12434438 (HIF-1α) select a population with a particularly poor outcome independently from the clinical effect of the two VEGF SNPs (PFS: 2.6 months, p < 0,0001; OS: 6.6 months, p < 0,0001). Conclusions: This investigation on HIF-1α SNPs, following our previous discoveries on VEGF and VEGFR, may represent a clinical tool to identify patients with favourable response to sorafenib. In the presence of a favourable genotyping, clinicians would administer sorafenib as soon as clinically indicated, instead of delaying it with other treatments. Conversely patients with unfavourable genotyping may not be optimal candidates for sorafenib. These patients should be preferably included in clinical trials exploring new treatment options.