Interferon-alpha therapy is effective in only approximately 20% of individuals with chronic HCV infection. A knowledge of the genetic and/or environmental factors that underlie this heterogeneity of response should provide useful predictors of clinical outcome. HCV infected patients and healthy subjects were selected from the expatriate Egyptian population living in Qatar, where chronic HCV infection poses a serious health problem. HCV infection was confirmed by ELISA and RT-PCR. Fifty five patients received interferon-alpha therapy for 6 months and their response was assessed by liver enzyme activity and histology of liver biopsies; the patient responses were followed during treatment and for 1 year afterwards. Twenty five patients were characterised as responders, and the remaining 30 as non-responders. All individuals in the study were typed for HLA class II alleles. Data were analysed by univariate and multivariate statistical methods. Expression of the HLA DR2 Major Histocompatibility class II allele is significantly associated with a beneficial response to interferon-alpha therapy in Egyptian patients (p < 0.005). This association is independent of cirrhosis, the absence of which also showed a significant association with response to therapy (p < 0.005). Our results therefore provide evidence that HLA DR2 is an important additional factor for predicting a long term response to interferon-alpha therapy in chronic HCV hepatitis.