To investigate the influence of immunogenetics on response to interferon (IFN)-alpha treatment, human leukocyte antigen alleles were characterized in 100 unrelated Taiwanese patients with chronic hepatitis C virus (HCV) infection. A11, B51, Cw15, and DRB1*15 were positively correlated with sustained response, whereas A24 was inversely associated with response to IFN-alpha, after adjustment for cirrhosis, pretreatment virus load, and viral genotype. Homozygote-genotype analysis showed that A24 and DQB1*05 probably had gene-dosage effect on sustained response. DRB1*15 was in strong linkage disequilibrium with DQB1*05 and DQB1*06, but only haplotype DRB1*15-DQB1*05 was associated with response to IFN-alpha. Haplotype A11-DRB1*15 was strongly associated with sustained response. This suggests a role for a complex host-immunogenetics interplay in the response to IFN-alpha, in patients with chronic HCV infection.