AbstractHost immune system genes play key roles in the progression of chronic hepatitis C virus (HCV) infection. Transporters associated with antigen processing (TAP) play an important role in the loading of viral peptides onto MHC class I molecules. This study aimed to investigate the association between TAP gene polymorphisms and chronic HCV in a Chinese Han population. A total of 232 chronic hepatitis C (CHC) patients and 362 healthy individuals were recruited from the Han population in Yunnan province in southwest China, and a TaqMan SNP genotyping assay was used to detect six single nucleotide polymorphisms (SNPs) of TAP1 and three SNPs of TAP2 genes. The association of the TAP gene with CHC was analysed at the allele, genotype, and haplotype levels. There were no significant differences in the allele and genotype frequencies of these SNPs in the TAP gene between CHC patients and controls after Bonferroni correction. A novel TAP1 allele (TAP1*unknown_1: rs41555220‐rs41549617‐rs1057141‐rs1135216‐rs1057149‐rs41551515: G‐G‐A‐G‐G‐G) was only present in the CHC group, and this allele significantly increased susceptibility to CHC (p = .005, odds ratio [OR] = 11.105. 95% confidence interval [CI]: 1.362–90.558). Homozygous TAP1*03:01/TAP1*03:01 was observed only in the CHC group that exhibited an obvious risk for CHC (p = .002, OR = 9.637, 95% CI: 1.153–80.574). And the haplotype TAP1*unknown_1‐TAP2*01:01 was only present in the CHC group and indicated a significant risk for CHC (p = .002, OR = 9.498, 95% CI: 1.140–79.149). We observed significant interactions among HLA‐A, ‐B,C, TAP1, and TAP2 alleles, and combination analysis revealed that the combination of TAP1*01:01‐TAP2*01:01‐HLA‐B*35:01 was only present in the control group (2.2%) and resulted in significantly increased resistance to CHC (p = .002, OR = 0.096, 95% CI: 0.012–0.759). Whereas, the combination of TAP1*01:01‐TAP2*01:01‐HLA‐C*07:02 and TAP1*03:01‐TAP2*01:01‐HLA‐C*01:02 increased the susceptibility to CHC significantly (p = .001, OR = 2.016, 95% CI: 1.309–3.106 and p = .002, OR = 8.070, 95% CI: 1.018–63.997, respectively). Our results indicated that TAP and HLA‐I may exert a combined effect on CHC susceptibility in the Chinese Han population.