To decrease transmission of hepatitis B virus (HBV), immunization with the HBV vaccine has been recommended for individuals in high-risk populations who are seronegative for antibodies to hepatitis B [1]. Isolated antibody to hepatitis B core antigen (antiHBc) seropositivity is found in about 2.5% of volunteer blood donors in the United States and is often considered a false-positive serological response [2]. However, in a retrospective review of HIV-infected patients in Worcester, Massachusetts, we unexpectedly noted isolated anti-HBc seropositivity in > 30% of our population. To gain insight into the meaning of the isolated anti-HBc seropositivity, we further analyzed this patient population.