The finding of a positive hepatitis B core antibody (anti-HBc) in the absence of hepatitis B surface antigen (HBsAg) or hepatitis B surface antibody (anti-HBs) is relatively uncommon. This finding is known to occur during the 'window period' of acute hepatitis B between loss of HBsAg and the appearance of anti-HBs. It may also occur with active infection or following resolution. The aim of this study was to determine if response to hepatitis B vaccination would allow the separation of these subgroups of patients with isolated anti-HBc. Seventeen patients with persistent isolated core antibody were vaccinated and serum obtained at 2, 4 and 8 weeks. Results were compared with a seronegative control group. Six subjects (35%) but no control patients (p = 0.016) responded with a titre of greater than 50mIU/mL at two weeks, suggesting an anamnestic response due to prior infection and immunity. A further seven subjects (41%) finally seroconverted (anti-HBs titre greater than 10mIU/mL) thus excluding chronic infection and suggesting initial false positive results. Only two subjects did not respond to a full course of vaccination, but neither they nor any other subjects were positive for HBV DNA. These results indicate that hepatitis B vaccination and subsequent measurement of anti-HBs will identify evidence of past infection in the form of an anamnestic response in up to one third of the patients and will also exclude chronic infection on the grounds of a normal vaccine response in a majority of the remainder.