SummaryHypertrophic cardiomyopathy (HCM) is a heart muscle disease characterized by hypertrophy and diastolic dysfunction of cardiac ventricles. It is suggested that one possible aetiology of HCM is the hepatitis C virus (HCV) infection, but molecular mechanisms underlying development of HCV‐associated HCM (HCV‐HCM) remains unknown. Because the human leucocyte antigen (HLA) molecule is involved in the control of progression/suppression of viral infection, extensive HLA allelic diversity may modulate the post‐infectious course of HCV and pathogenesis of HCV‐HCM. Here we undertook a case‐control study with 38 patients with HCV‐HCM and 132 unrelated healthy controls to reveal the potential impact of polymorphisms in seven classical and two non‐classical HLA genes on the pathogenesis of HCV‐HCM. It was found that DPB1*0401 and DPB1*0901 were significantly associated with increased risk to HCV‐HCM in dominant model (P < 0.028, OR = 3.94, 95% confidence interval (CI) = 1.19, 13.02) and in recessive model (P < 0.007, OR = 9.85, 95% CI = 1.83, 53.04), respectively. The disparity in the gene–dose effect by two susceptible DPB1 alleles may be attributable to the difference between the susceptible (36 A and 55 A) and resistant (8L, 9F, 11G, 57E and 76M) residue‐combination consisting of DPβ anchor pocket for antigenic peptide‐binding. These results implied that the HLA‐DP molecules with specificity pocket appropriate for HCV antigen(s) might confer the progressive process of HCM among the HCV‐infected individuals.