The influence of highly active antiretroviral therapy (HAART) upon hepatitis B virus (HBV) vaccine responses in HIV-infected individuals is unclear. After classification of vaccinees as non-responders (HBsAb <10IU/L) or responders (HBsAb >or=10IU/L) in our HIV cohort, multivariate logistic regression was used to assess factors associated with subsequent vaccine response. Of 626 participants vaccinated from 1988 to 2005, 217 (35%) were vaccine responders. Receipt of >or=3 doses of vaccine (OR 1.83, 95% CI 1.24-2.70), higher CD4 count at vaccination (OR 1.09, 95% CI 1.05-1.13 per 50 cells/microl increase), and use of HAART (OR 2.37, 95% CI 1.56-3.62) were all associated with increased likelihood of developing a response. However, only 49% of those on HAART at last vaccination responded, and 62% of those on HAART, with CD4 count >or=350, and HIV RNA <400 copies/mL responded. Compared to those on HAART with CD4 count >or=350, those not on HAART with CD4 count >or=350 had significantly reduced odds of developing a vaccine response (OR 0.47, 95% CI 0.30-0.70). While HAART use concurrent with HBV immunization was associated with increased probability of responding to the vaccine, the response rate was low for those on HAART. These data provide additional evidence of HAART benefits, even in those with higher CD4 counts, but also highlight the need for improving HBV vaccine immunogenicity.