Diabetics are at higher risk of infection with hepatitis B and the CDC recommends routine vaccination. Existing vaccines have important limitations including reduced compliance with 3 doses and reduced efficacy in type 2 diabetics. HEPLISAV-B combines recombinant hepatitis B surface antigen (20μg) with an oligonucleotide toll-like receptor 9 (TLR9) agonist as an adjuvant. A phase 3 study evaluated the safety and immunogenicity of HEPLISAV-B compared with Engerix-B. In a randomized, multicenter, observer-blinded study, immunogenicity at week 28 was a co-primary endpoint in type 2 diabetics who received either 3 doses of Engerix-B (n=321) at weeks 0, 4 and 24 or 2 doses of HEPLISAV-B (n=640) at weeks 0 and 4 (plus placebo at week 24). Among the 961 adult diabetics in the per-protocol population, age, sex and race were generally similar across both treatment groups. In both groups 2/3 of subjects had diabetes for 5 or more years. The proportion of protected subjects (protected=anti-hepatitis B antibody titers ≥ 10mIU/mL) in the HEPLISAV-B group at week 28 was 90.0% (95% CI: 87.4%, 92.2%) vs. 65.1% (95% CI: 59.6, 70.3) in the Engerix-B group. The difference between the groups, 24.9% (95% CI: 19.3%, 30.7%), was statistically significant. The safety profile including the incidence of immune-mediated adverse events was similar in both treatment groups. HEPLISAV-B protected a statistically significantly higher proportion of subjects with diabetes against hepatitis B when compared with Engerix-B. HEPLISAV-B may be able to address a significant unmet medical need in diabetics who should be routinely vaccinated against hepatitis B.