Two distinct serologic types of chronic hepatitis B have been identified, namely the "classical" HBeAg positive form and the "atypical" HBeAg negative, anti-HBe positive variant which is due to infection by a mutant HBV having a pre-core stop codon that makes the virus unable to produce HBeAg. The anti-HBe positive form is currently the prevalent type of chronic hepatitis B in the Mediterranean area, being associated with a more severe clinical course compared to HBeAg positive cases. The response to interferon therapy in patients with anti-HBe positive chronic hepatitis B has been recently investigated in control trials. These studies have shown that normalization of ALT with efficient suppression of virus activity can be achieved in 50-80% of patients while treated with interferon alpha indicating that also the pre-core mutant of HBV is sensitive to the antiviral effect of interferon. However, reactivation of hepatitis occurs in a variable percentage of initial responders when interferon is stopped. The probability of reactivation increases when the disease is of long duration, when cirrhosis is present and particularly if the pre-core mutant of HBV has become the predominant type of circulating virus, indicating that this HBV variant is more resistant to immunoclearance compared to wild type HBV.