Hepatitis C outcome is likely related both to viral factors and host's immune responses. We correlated the severity of liver disease with human leukocyte antigen (HLA) genes (C4A, C4B, TNFA, TNFB, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, TAP1, and TAP2) in three groups of subjects: 99 patients with chronic hepatitis, 41 asymptomatic carriers, and 179 uninfected controls. Patients with grade/stage 3 to 4 hepatitis significantly differentiated for their low frequency of alleles TNFB*1, DRB1*1104, and DRB3*03, which had a protective role, and high frequency of allele DRB1*1001, which was associated with disease severity. HLA-DRB*11 subtypes were differentially distributed: DRB1*1104 was most frequent in carriers, whereas DRB1*1101 was more frequent in patients. The TAP1C,2A haplotype was also underrepresented in patients with respect to controls. Finally, a decrease of heterozygous subjects was observed in patients with respect to carriers at the DQB1 locus. Multivariate analysis by correspondence analysis and multiple logistic regression indicated that age, sex, and hepatitis C virus (HCV) type were the strongest risk factors; however, some immunogenetic variables (TNFB*1, DRB1*1104, and DRB3*03) showed an independent contribution, especially in comparing patients with extreme manifestations of disease. The involvement of different genes in various HLA subregions suggests that anti-HCV responses are modulated by a complex gene interplay rather than by single alleles. (HEPATOLOGY 1999;29: 1272-1279.)Hepatitis C virus (HCV) is the major cause of chronic liver disease in Italy and accounts for over 70% of cirrhosis and hepatocellular carcinomas. 1 HCV infection results in high rates of chronicization and in a broad spectrum of liver lesions, ranging from mild inflammation to liver failure.Mechanisms underlying viral persistence and liver damage in chronic HCV infection are marginally known, a complex interplay of viral and immunologic factors being likely involved. Immunomediated mechanisms are believed to play a major role, 2-4 as is suggested by the lack of evidence for a cytopathic effect of the virus, 2 the severe course of infection in immunosuppressed patients, 5 the frequent occurrence of immunologic disorders, 6 and the cytokine-mediated expression of immunoregulatory molecules in the infected liver. 7