Fifty-five drug users institutionalized in a community for drug detoxification were vaccinated against hepatitis B virus (HBV) with a recombinant yeast-derived vaccine (Engerix B, Smith Kline Biologicals, Belgium). At 0, 1, and 6 months, 20 micrograms of vaccine was given in the deltoid to these patients, of whom 17 had no serum HBV markers, 15 had only the antibody to core antigen (anti-HBc), and 23 had anti-HBc and antibody to the surface antigen (anti-HBs) values lower than the allegedly "protective" value of 10 mIU/mL. Forty-one healthy controls were vaccinated in parallel. At month 7 (ie, 1 month after the third dose of vaccine), in 76% (13/17) of drug users with no HBV markers, 6% (1/15) of those with isolated anti-HBc, and 69% (16/23) of those with anti-HBc and nonprotective anti-HBs, protective anti-HBs titers (greater than or equal to 10 mIU/mL) developed, compared with 97% (40/41) of controls. At month 24, these rates fell to 43% for drug users with no HBV marker, 0% for those with anti-HBc, 31% for those with anti-HBc and anti-HBs, and 86% for controls. The drug users who did not respond to vaccination were more likely to be those with evidence of prior HBV infection and anergy to skin tests. This indicates that unresponsiveness to hepatitis B vaccine in drug users may be due to altered immunity.