A large percentage of human immunodeficiency virus (HIV) patients have serological evidence of a past or present hepatitis B virus infection (HBV). Long-term survival is increasing for HIV patients because of highly active antiretroviral therapy. Therefore, the chronic hepatitis B infection may become an important determinant of disease outcome in these co-infected patients. We describe two HIV/HBV co-infected patients who were treated with extended antiviral therapy, initially indicated for the HIV infection. Lamivudine, a suppressor of viral replication in both infections, was one of these antiviral drugs. One patient showed a severe rebound of the HBV after withdrawal of lamivudine, the other patient developed a mutant hepatitis B virus after 18 months of treatment. This mutation was exclusively induced by lamivudine. These patients show that, with improved HIV-related survival, the HBV infection should be monitored carefully, thereby enabling the physician to interfere with therapy when necessary.