Hepatitis C virus (HCV)-host interaction, namely the host immune reaction against various viral proteins, determines viral persistency and the severity of liver damage. The strong lymphotropism of HCV has been proven to be responsible in part for its ability to evade the peripheral immune response and possibly the frequency of HCV-related autoimmunity. Various mechanisms were reported to be responsible for HCV persistency and its association with autoimmunity. Of these, enhanced T cell apoptosis was reported to contribute to viral persistency and disease severity. The issue of HCV-related autoimmunity has partly been shown to be related to the resistance of CD5+ B cell subpopulation to apoptosis. Autoimmunity has been reported by many to include a wide range of autoantibodies such as rheumatoid factor, ani-cardiolipin and smooth muscle antibodies. In this review our aim is to summarize the data on the mechanisms responsible for HCV persistence and HCV-related autoimmunity. We will try to determine the importance of autoimmunity in the evaluation of chronic HCV infected patients.