Background & Aims The study aimed to evaluate the tissue expression of molecules involved in intracellular signalling pathways as predictors of response to sorafenib in advanced hepatocellular carcinoma (HCC). Methods We considered 77 patients enrolled into three prospective trials of sorafenib treatment for whom pretreatment tumour tissue was available. The tissue expression of β‐catenin, glutamine synthetase (GS), phosphorylated extracellular signal regulated kinase (pERK), phosphorylated v‐akt murine thymoma viral oncogene homolog (pAKT) and vascular endothelial growth factor receptor‐2 (VEGFR‐2) was analysed by immunostaining. Stains were scored semiquantitatively and compared with a reference group of 56 untreated HCCs. Results Overall, the expression of antigens was comparable between treated and untreated patients. Shorter progression‐free survival (PFS) and overall survival (OS) were associated with increased pERK staining (≥ 2+ scores) (PFS: 75th percentile 4.4 vs 8.4 months; P = 0.01; OS: 75th percentile 7.0 vs 15.0 months; P = 0.005) and VEGFR‐2 staining (≥ 2+ scores) (PFS: 75th percentile 3.8 vs 7.0 months; P = 0.039; OS: 75th percentile 6.3 vs 15.0 months; P = 0.004). At multivariate analysis, both pERK and VEGFR‐2 staining maintained an independent effect on OS (HR 2.09; 95% CI, 1.13–3.86, P = 0.019 and HR 2.28; 95% CI, 1.13–4.61, P = 0.021 respectively). No effect was observed for the other tested biomarkers. Conclusions Elevated tissue expression of pERK and VEGFR‐2 was predictive of poor outcome in advanced HCC treated with sorafenib.