Whether the host's immune response genes influence the severity of hepatitis C virus (HCV) liver disease is controversial. Human leukocyte antigen (HLA) class II alleles were analyzed in 233 HCV RNA-positive patients with chronic active hepatitis (197 patients with Knodell index of fibrosis F0-F3 and 36 patients with index of F4). The 2 groups did not differ by sex, duration of infection, mode of contamination, alcohol consumption, or HCV genotype. Patients with cirrhosis were older than those without (56+/-12 vs. 46+/-14 years; P<10-4) and had a lower DRB1*11 allele frequency (5.6% vs. 14.5%; P=.037), whereas DRB1*03 and DQB1*0201 frequencies appeared to be higher (DRB1*03, 18.1% vs. 9.6%; DQB1*0201, 37.5% vs. 23.4%; P=.04, corrected P value is not significant). Mean index of fibrosis was higher in DR3-positive than in DR11-positive patients (2.14 vs. 1.58; P=.05). By multivariate analysis, cirrhosis was associated with male sex and age >50 years. HLA class II alleles may weakly contribute to the severity of HCV liver disease. Of persons infected with HCV, only 15%-20% spontaneously clear the virus, and the rest become chronically infected.