Hepatitis B surface antigen (HBsAg) seroclearance in chronic HBV infection occurs at an annual incidence of 1-2%. The long-term outcome after HBsAg seroclearance is excellent if there is no pre-existing cirrhosis or viral superinfection. For this reason, HBsAg seroclearance has attracted recent interest in both long-term studies of the natural history of HBV infection and in patients receiving antiviral therapy. Here, we review a diverse range of studies investigating spontaneous HBsAg seroclearance in varied groups of patients and consider the many predictive factors - of both viral and host origin - for seroclearance. Studies to assess the effects of antiviral therapy, and in particular interferon treatment, are also discussed together with virological, biochemical and histological profiles following HBsAg seroclearance and the long-term outcomes.