Chronic hepatitis C virus (HCV) infection is a major risk factor for hepatocellular carcinoma (HCC). HCV proteins core and NS3 can bind to toll-like receptor 2 (TLR2) and trigger inflammatory responses. Polymorphisms in theTLR2gene predispose to various forms of malignancy but have not been studied in HCV-associated HCC. Here, we investigated whether single nucleotide polymorphisms (SNPs), rs4696480, rs5743708, rs5743704 and the -196 to -174 del/ins polymorphism of theTLR2gene affect the risk for HCC in chronic hepatitis C. The study involved 189 and 192 HCV genotype 1 infected patients with and without HCC, respectively, as well as 347 healthy controls.TLR2alleles were determined by hybridization probe assays and allele-specific short fragment polymerase chain reaction on a LightCycler system. AllTLR2polymorphisms matched the Hardy–Weinberg equilibrium in each study group. AlthoughTLR2SNPs showed no effect, the frequency of theTLR2-196 to -174 del allele was significantly higher in patients with HCV-associated HCC (22.5%) than in HCV-infected patients without HCC (15.6%,p= 0.016) and healthy controls (15.3%,p= 0.003). HCV-infected carriers of aTLR2-196 to -174 del allele had significantly higher HCV viral loads thanTLR2-196 to -174 ins/ins homozygous patients (p= 0.031). Finally, in carriers of theTLR2-196 to -174 del allele, stimulation of monocytes resulted in significantly lower TLR2 expression levels and interleukin-8 (IL-8) induction than in individuals with theTLR2-196 to -174 ins/ins genotype (p< 0.05). Our data suggest theTLR2-196 to -174 del allele to affect HCV viral loads and to increase the risk for HCC in HCV genotype1-infected patients.