As a class, tumor necrosis factor (TNF)-alpha inhibitors have provided clinicians significant control over chronic inflammatory diseases. With their widespread use has come the emergence of new side effects such as the reactivation of latent infections. One such infection that may reactivate is the hepatitis B virus (HBV). It is currently unknown if HBV reactivation is a class effect or attributable to a particular TNF-alpha inhibitor. To answer this question, a comprehensive literature review to identify trends in related cases was performed. A systemic literature review was performed using the PubMed and Medline databases (1996 to January 2010) searching for the index term "Hepatitis B" combined with the terms "tumor necrosis factor," "TNF-alpha inhibitors," "etanercept," "adalimumab," "certolizumab," and "golimumab." All relevant articles in English were reviewed, and secondary references of interest were also retrieved. Thirty-five cases with hepatitis B surface antigen (HBsAg) positivity known prior to initiation of TNF-alpha inhibitors were identified. Infliximab was used in 17 cases, etanercept in 12 cases, and adalimumab in 6 cases. All six cases of clinically symptomatic hepatitis were associated with infliximab therapy. Infliximab was associated with the most cases of greater than 2-fold increase in alanine aminotransferase (six of nine cases) and greater than 1,000-fold increase in HBV DNA load (three of four). The two deaths reported occurred with infliximab therapy. Potential mechanisms of action for the reported observations include differences in molecular design, route of administration, and potency in clearing TNF-alpha. In patients with a positive HBsAg prior to starting a TNF-alpha inhibitor, infliximab has the most reported cases associated with HBV reactivation. While such reactivation may be due to a variety of reasons, clinicians prescribing TNF-alpha inhibitors to HBsAg-positive patients should consider prophylactic antiviral therapy and close monitoring for any clinical or serological evidence of hepatitis.