© 2017 Morsica et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background and aim: Antibodies against hepatitis B core antigen (anti-HBc) are found in 14–44% of patients with HIV infection, but it is still unclear whether hepatitis B virus (HBV) vaccination should be recommended for HIV-positive subjects with isolated anti-HBc (IAHBc). We examined the rate of anamnestic and primary responses (ARs and PRs) and associated factors in a group of HIV-infected patients with an IAHBc profile. Methods: This prospective study recruited 25 HIV-positive patients with anti-HBc alone who were vaccinated against HBV infection. Those without an AR (anti-hepatitis B envelope antigen [anti-HBs] levels of <10 U/L) or who were hypo-responsiveness (anti-HBs levels of > 10 but <100 U/L) four weeks after the first dose of vaccine underwent a full course of vaccinations. Th eir clinical and virological data, including the presence of occult hepatitis B infection (OBI), were evaluated in accordance with the vaccination schedule. Results: Six of the 25 patients (24%) showed an AR, four of whom had anti-HBs levels of <100 U/L. Ten of 19 (52.6%) remaining patients became seroprotected after the third dose. OBI was detected in four of the six patients with an AR, two of the 10 patients with a PR, and none of the nine patients who did not respond. Multivariate analysis showed that an AR was associated with the presence of OBI (P = 0.0162), and a PR was associated with HCV antibody status. (P = 0.0191). Conclusions: Our data suggest that testing for anti-HBc alone may not be a reliable means of assessing protection from HBV infection in HIV-positive patients. OBI-positive patients may benefit from a single vaccine dose. Anti-HCV serostatus may affect PRs. © 2017 Morsica et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.