Antibodies to the pre-S2 encoded sequence of the hepatitis B virus (HBV) envelope were detected in 83% of patients recovering from acute hepatitis B. Such antibodies were absent in cases showing chronic evolution and were found in less than 10% of chronic hepatitis B cases, with no relation to liver disease activity. In acute infection anti-pre-S2 became detectable when maximum liver damage had already occurred and was still detectable in 30% of the cases tested 5-7 years after recovery, as well as in 40% of healthy individuals with naturally acquired immunity to HBV. 10 out of 20 recipients of a plasma-derived, pre-S2-containing, HB vaccine acquired anti-pre-S2 and had no evidence of concurrent liver damage or of autoimmune reactions to human albumin or of suppression of the anti-HBs response. These findings indicate that the antibody response to pre-S2 is a marker of HBV clearance and has no role in the pathogenesis of HBV-related liver damage.