Anti-tumor necrosis factor-alpha (TNF) therapy has recently been recognized to be associated with activation of hepatitis B virus (HBV) infection, with a potentially fatal outcome, mirroring experience in the setting of immune suppression and subsequent reconstitution in cancer chemotherapy and transplantation. Although there is no current evidence that anti-TNF therapy influences the natural history of hepatitis C virus (HCV) infection, the involvement of TNF in the pathogenesis of hepatic injury and extrapolation from other clinical situations heighten awareness of a potential conflict. Preventive strategies should be mandatory. These include screening of all patients for HBV and HCV infection prior to commencement of anti-TNF therapy, and active monitoring of aminotransferases and, for HBV, viral load during and for 3 months after therapy has terminated. Prophylactic or early intervention strategies with nucleoside analogs are recommended for patients with evidence of HBV infection.