The significance of antibody to hepatitis B core antigen (anti-HBc) present in a person's serum without hepatitis B surface antigen (HBsAg) or its antibody (anti-HBs) is unknown. Serum specimens from 281 persons initially positive only for anti-HBc by enzyme immunoassay (EIA) were retested by radioimmunoassay (RIA), and of these, 177 (63%) remained positive for anti-HBc by both assays. Of these 177 persons, 3 were positive for HBsAg, and 72 possessed low levels of anti-HBs [less than 10 sample ratio units; (SRU's)]. When persons positive for anti-HBc by EIA and RIA were given one 20-micrograms dose of plasma-derived hepatitis B vaccine and tested for anti-HBs 1 month later, a booster response was observed in 14 of 41 (34%) persons with low level anti-HBs and 3 of 50 (6%) persons negative for anti-HBs. Of those positive only for anti-HBc by EIA but negative by RIA, only 3 of 37 (8.1%) showed a booster response. Of those who completed the three-dose immunization series and did not show a booster response, 63 of 80 (78.8%) developed anti-HBs levels greater than 10 standard ratio unit. The majority of persons with isolated anti-HBc will have a primary rather than a booster response to hepatitis B vaccine.