The response to interferon (IFN) therapy in patients with chronic hepatitis C is characterized by normalization of the serum alanine aminotransferase (ALT) activity during treatment, but relapse within 6 months of cessation of therapy is common. Viral characteristics, such as the genotype and viral load, may influence the patient response to IFN. The aim of this study was to examine host factors, namely the genetically determined human leucocyte antigen (HLA) class II alleles, in patients with chronic hepatitis C, and their relationship to the response to IFN therapy. Seventy white patients with chronic hepatitis C, treated with IFN-alpha for 6 months, were enrolled in the study. Serum ALT was measured at the end of treatment to assess short-term response and again 6 months post-treatment to assess sustained response. Sequence-specific primers were used in the polymerase chain reaction (PCR) to amplify genomic DNA isolated from peripheral mononuclear cells. HLA class II alleles were determined by analysis of the amplicon by gel electrophoresis and hybridization of sequence-specific oligonucleotide probes. At the end of treatment, 25 of the 70 patients (36%) had a normal ALT. By 6 months post-treatment, only six patients (9%) had a sustained normalization of ALT. The frequency of the allele DRB1*0404 was significantly higher in patients with a sustained response as compared to those lacking such a response (25.0% vs 2.3%, with a Bonferonni-corrected P-value of 0.019). There was no difference in the frequency of other class II alleles at the DRB1 and DQB1 loci in responders as compared with non-responders. Therefore, we conclude that the maintenance of a response to IFN in chronic hepatitis C may be, in part, determined by genetic factors in the host.