CD20 is a 33-kD B-cell antigen that is expressed from the early pre-B-cell stage of development and is lost on differentiation of B cells into plasma cells. Because CD20 is expressed strictly by B cells, it is an attractive target for B-cell lymphoma therapy. Monoclonal antibodies to CD20 have been used successfully in the treatment of B-cell lymphomas. We hypothesized that a vaccine consisting of CD20 peptide sequences might be capable of inducing an active, specific, humoral immune response to the protein. Vaccine therapy would have the advantage of generating a polyclonal response to the antigen in contrast to the monoclonal response of an infused antibody. Balb/c mice were vaccinated with prototype vaccine constructs that consisted of peptides representing the human or mouse CD20 extracellular sequences conjugated to carrier proteins and mixed with QS21 adjuvant. Sera from the vaccinated mice demonstrated high-titer, specific antibodies to various epitopes on the immunizing peptides in enzyme-linked immunosorbent assay, weaker antibody binding to native CD20 on cells by flow cytometry, and antibody-mediated complement killing of CD20(+) cells in some cases. Specific proliferation and secretion of interleukin 4 and interferon gamma by mouse spleen cells in response to the immunizing peptides were also demonstrated. Mice vaccinated with the CD20 peptide keyhole limpet hemocyanin conjugates had a 25% decrease in CD19(+) splenic B cells relative to control mice. These data indicate that a biologically active, specific immune response to CD20 can be elicited in mice vaccinated with CD20 peptide conjugates.