<b><i>Background:</i></b> Although human leukocyte antigens (HLA) have been shown in association with the outcomes of hepatitis C virus (HCV) infection among different ethnic groups, such studies remain absent in China, where the HCV prevalence is higher than the global average. <b><i>Methods:</i></b> In this study, 426 HCV-infected and 709 uninfected blood donors were analyzed, among whom the HLA alleles were sequenced using a high-resolution genotyping method. <b><i>Results:</i></b> At the 2-digit level, none of the alleles showed a statistical difference between the HCV-infected and uninfected groups. However, at the 4-digit level, the HLA-B alleles B*15:01 and B*15:02 showed an opposite association with HCV infection, i.e. B*15:01 was significantly higher in the HCV-infected group (odds ratio, OR = 1.561, p = 0.010), while B*15:02 was significantly higher in the uninfected group (OR = 0.778, p = 0.016). We also identified a higher frequency of B*13:02 in the HCV-infected group (OR = 1.515, p = 0.009) and a higher frequency of B*07:05 in the uninfected group (OR = 0.299, p = 0.001). <b><i>Conclusions:</i></b> The frequencies of four HLA alleles, B*07:05, B*13:02, B*15:01, and B*15:02, were found to be significantly different between the HCV-infected and uninfected blood donors in China, revealing an inverse relation of B*15:01 and B*15:02 with HCV infection. This finding suggests that the ethnic genetic variations of HLA may greatly affect the host immune responses against HCV.