This prospective study enrolled healthcare workers (HCW) who were nonresponders following at least 5 doses of aluminum-adjuvanted hepatitis B vaccine received the 2-dose Heplisav-B (HepB-CpG) series. After two doses of HepB-CpG, 43/47 (91%) participants, and with 1 dose 41/49 (84%) responded. HepB-CpGcould be the preferred vaccine in HCW nonresponders.