The ability of three doses of a novel MF59-adjuvanted hepatitis B virus (HBV) vaccine containing surface and pre-S2 antigens given at 0, 1, and 6 months to induce levels of HBV surface antibody (sAb) > or = 100 mIU/ml was compared with a UK licensed alum-adjuvanted yeast-derived HBV vaccine in HBV-naive healthcare workers (HCWs). One month after second immunization with HBV/MF59, 100% of HCWs had sAb > or = 100 mIU/mL, compared with only 11% and 85% after two or three immunisations with Engerix-B. The sAb GMT of the Engerix B immunised group remained below 100 mIU/mL until month seven, (compared with month one for HBV/MF59), and was 123-fold lower at this time (208,561 vs. 1,686 mIU/mL). In our subjects HBV/MF59 vaccine rapidly induced sAb to levels far in excess of those recommended by the Department of Health for high-risk situations (e.g. HCWs and patients on dialysis). It has the potential for shorter schedules and reduced need for serology and boosters.