Due to the relation between lipids and Hepatitis C virus (HCV) life-cycle, we aimed to explore the existence of single nucleotide polymorphisms (SNPs) associated with low susceptibility to HCV-infection within lipid metabolism genes. This was a case-control study in three phases: (I) allelic frequencies of 9 SNPs within 6 genes were compared in 404 HCV-infected patients and 801 population controls; (II) results were validated in 602 HCV-infected individuals and 1352 controls; (III) results were confirmed in 30 HCV-exposed uninfected (EU) individuals. In phase I, only the LDLRAP1-rs4075184-A allele was differentially distributed in patients and controls (358 of 808 alleles [44.3%] and 807 of 1602 alleles [50.3%], respectively) (p = 0.004). In phase II, the A allele frequency was 547 of 1204 alleles (45.4%) in patients and 1326 of 2704 alleles (49.0%) in controls (p = 0.037). This frequency in EU was 36 of 60 alleles (60%), which was higher than that observed in patients from phase I (p = 0.018) and phase II (p = 0.027). The LDLRAP1-mRNA expression was lower in AA carriers than in non-AA carriers (median [Q1-Q3]: 0.85 [0.17-1.75] relative-units [ru] versus 1.71 [1.00-2.73] ru; p = 0.041). Our results suggest that LDLRAP1-rs4075184-A allele is associated with lower susceptibility to HCV-infection and with reduced expression of LDLRAP1-mRNA.