Although vaccination against hepatitis B virus (HBV) is highly successful, 5% to 10% of individuals do not experience a response with an adequate antibody level to hepatitis B surface antigen (anti-HBs). Contributing causes for nonresponse to the vaccine are genetic predisposition, immunosuppression, and certain chronic illnesses. The distinction between true nonresponse (after adequate immunization) and waning anti-HBs levels is important. The latter is not uncommon in populations in areas of the world with low endemicity for HBV infection. Data from subjects with waning anti-HBs levels show that immunologic memory may still protect these individuals against acute HBV infection or may prevent chronic infection with HBV for < or =10 years after immunization. Recent reports from Asia and Alaska describe cases of chronic HBV infection 15 years after immunization in subjects who have very low levels of anti-HBs. Thus, nonresponders or those with waning immunity who may be at risk of HBV infection in subsequent years may require a booster dose. Clinical algorithms to reimmunize nonresponders have been described and are discussed in this article. Experimental hepatitis B vaccines have shown some promise in nonresponders but are not commercially available in the United States.