The human leukocyte antigen is a crucial genetic factor that initiates or regulates immune response by presenting foreign or self antigens to T lymphocytes. The aim of this study was to investigate whether HLA polymorphism is associated with the onset or progression of liver injury in chronic hepatitis C virus (HCV) infection. We determined HLA class I antigens and class II alleles in 130 hepatitis C virus (HCV)-infected patients (33 carriers with persistently normal alanine transaminase [ALT] values and 97 patients with chronic liver disease [CLD]). HLA class I (A, B) was typed serologically, and class II (DRB1, DQB1) was typed by means of polymerase chain reaction–restriction fragment length polymorphism methods. The frequencies of DRB1*0405 and DQB1*0401 were higher in HCV-infected patients than in uninfected subjects. Among HCV-infected patients, the frequencies of B54, DRB1*0405, and DQB1*0401 were significantly higher in patients with CLD than in those carriers with persistently normal ALT values, whereas DRB1*1302, DRB1*1101, and DQB1*0604 were more frequently found in carriers with persistently normal ALT values than in patients with CLD. From extended haplotype analyses, in carriers with B54-DRB1*0405-DQB1*0401 haplotype, the risk of having liver injury was 13.2 times greater than in carriers with DRB1*0405-DQB1*0401 but without B54 [P = 0.0015, Haldane odds ratio = 13.2 (95% confidence interval, 1.7–103.8)]. In contrast, carriers with B44-DRB1*1302-DQB1*0604 had a 12.7-fold lower relative risk of developing liver injury compared to those with the haplotype containing B44 but not DRB1*1302-DQB1*0604 [P = 0.0076, Haldane odds ratio = 0.079 (0.009–0.695)]. Our findings show that extended haplotypes including class I B54 are closely associated with the progression of liver injury, whereas extended haplotypes including class II DRB1*1302-DQB1*0604 are associated with low hepatitis activity in chronic HCV infection.