Serial sera were collected prospectively during the clinical course of 13 HBsAg carriers with chronic liver disease and analyzed for ALT levels, pre-S1 and pre-S2 antigens and corresponding antibodies and other serological hepatitis B virus markers. In five patients, anti—pre-S1 and anti—pre-S2 antibodies became detectable in multiple serum samples, whereas in eight patients anti—pre-S was never detected or only appeared transiently during the follow-up. The first pattern was associated with normalization of ALT levels and undetectable pre-S antigens and viral DNA by the polymerase chain reaction assay at final follow-up. HBsAg clearance occurred in two of the five patients. The second pattern was one of persistence of HBsAg and pre-S antigens, associated with the presence of serum HBV DNA detectable by spot hybridization or polymerase chain reaction regardless of clinical outcome. These findings demonstrate the occurrence of anti—pre-S antibodies in chronic hepatitis B virus—induced liver disease and associate anti—pre-S appearance with the clearance of hepatitis B virus from serum. (HEPATOLOGY 1992;15:26–31).