<i>Objective:</i> Toll-like receptor 4 (TLR4) signalling participates in the innate immune response against hepatitis C virus (HCV) infection. <i>TLR4 </i>gene polymorphisms may influence the risk of HCV-induced hepatocellular carcinoma (HCC). This is a single-centre-based study designed to analyse the distribution of several <i>TLR4 </i>gene single nucleotide polymorphisms in healthy controls and in patients chronically infected with HCV, with and without HCC. <i>Methods:</i> We have determined three single nucleotide polymorphisms (rs2149356, rs4986791 and rs5030719) at the <i>TLR4</i> gene in 155 patients with HCV-related HCC, 153 patients with chronic hepatitis C and 390 healthy controls. All were white and most were Spaniards. <i>Results:</i>(1) rs5030719 was monomorphic and was not further analysed; (2) the rs2149356 T allele carrier state was significantly less frequent in patients with HCC than in healthy controls (OR 0.421, 95% CI 0.285–0.625) and in patients with chronic hepatitis C (OR 0.426, 95% CI 0.236–0.767); (3) the proportion of rs2149356 T allele carriers progressively diminished with increasing clinical stage of HCC; (4) no significant differences were observed for the rs4986791 T allele. <i>Conclusion:</i> The <i>TLR4 </i>rs2148356 T allele is associated with a reduced risk of HCC and could slow down its clinical progression in HCV-induced chronic liver disease.