This study describes results of a multi-country phase 3, open-label randomized trial evaluating HepB-CpG immunogenicity among 561 participants with HIV on ART who were hepatitis B vaccine “non-responders.” Investigators compared seroprotection response after 2 doses of HepB-CpG versus 3 conventional doses (20µg recombinant HBsAg) of HepB-alum vaccine, as well as response after 3 doses of HepB-CpG. Participants were adults (median age 46 years) with CD4 ≥ 100 cells/µL (median 638 cells/µL) and HIV RNA less than 1000 copies/mL (94% had RNA less than 40 copies/mL); 64% were male and 13% had diabetes. Time since previous hepatitis B vaccination was greater than 10 years for 42%, and 24% had received more than 3 doses. A seroprotection response was achieved in 93.1% of participants in the 2-dose HepB-CpG group, 99.4% in the 3-dose HepB-CpG group, and 80.6% in the 3-dose HepB-alum group. Based on stratified analyses, both 2-dose and 3-dose HepB-CpG were superior to 3-dose HepB-alum. Further, seroprotection response was achieved more rapidly in participants receiving HepB-CpG, and 78.1% in the 3-dose HepB-CpG group achieved titers greater than 1000 mIU/mL. Participants who were older, reported White race, or had lower CD4 cell counts were less likely to achieve a seroprotection response.