On the basis of theoretical considerations, a peptide (H peptide) was synthesized by Hopp and Woods [Hopp, T. P. & Woods, K. R. (1981) Proc. Natl. Acad. Sci. USA 78, 3824---3828]. This peptide contains a sequence of six amino acids postulated to represent the major epitope, or antibody-combining site, of hepatitis B virus surface antigen (HBsAg). We have used passive hemagglutination inhibition with monospecific antibodies against the a, d, and y subdeterminants of this antigen and against human serum albumin to investigate the antigenic specificities on this peptide, and we have found it to contain the HBsAg/a and HBsAg/d but not HBsAg/y or human serum albumin subdeterminants. When the peptide was conjugated onto human erythrocytes and injected into mice, it induced the formation of anti-HBsAg with and without the use of Freund's adjuvant. If anti-HBsAg/a confers immunity to infection with hepatitis B virus, as is generally thought, these findings may permit the development of a synthetic vaccine lacking all unnecessary antigenic determinants.