The immunobiology of hepatitis C virus (HCV) is significantly influenced by the host immune response to the virus, especially by virus-specific T-cell responses. Virus-specific T cells are restricted by human leucocyte antigen class I and II molecules. Of note, associations between these polymorphic loci and outcome and course of HCV infection have been reported in large and well-documented cohorts. This review will briefly summarize these studies and focus especially on the immunological and virological basis for the reported associations. The outcome and course of HCV infection is most likely determined by a complex interplay of genetic, immunological and virological factors. A better understanding of these host-virus interactions is essential not only to gain better insights into the mechanisms of viral clearance and persistence but also for the development of new antiviral vaccine strategies.