Vitamin D binding protein (VDBP) plays an important role in the immune modulation and pathogenesis of hepatitis C viral (HCV) infection by influencing serum vitamin D levels. The present study aims to evaluate the association of VDBP genetic polymorphisms with susceptibility to and chronicity of HCV infection in a high-risk Chinese population. Seven genetic variants in the VDBP gene were genotyped in a case-control study of 886 patients with HCV persistent infection, 539 subjects with spontaneous clearance, and 1081 uninfected controls. Logistic regression analysis was used to assess the effects of these variants on HCV infection outcomes. The results showed that two variants rs7041-G and rs3733359-T alleles were significantly associated with increased susceptibility of HCV infection, and the combined effect of the two unfavorable alleles was related to an elevated risk of HCV infection in a locus-dosage manner (Ptrend = 8.16 × 10-4). Interaction analysis manifested that rs7041-GT/GG and rs3733359-CT/TT jointly increased risk of HCV infection. Moreover, haplotype analysis suggested that compared with the most frequent TC haplotype, the haplotype carrying GT indicated a risk effect of HCV infection [odds ratio (OR) = 1.464]. However, no significant associations were observed for the other five variants. These findings implied that VDBP rs7041-G and rs3733359-T variants may contribute to increased susceptibility to HCV infection in a high-risk Chinese population. Copyright © 2018 Elsevier B.V. All rights reserved.