A fusion protein containing a B cell lymphoma idiotype (Id) and granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent stimulator of tumor immunity. In three different tumor models we show that immunization with autologous lymphoma cells that have been engineered to express the Id in the context of GM-CSF is much more effective than immunization with an equivalent dose of the purified protein. The lymphoma Id could be modified by introducing the GM-CSF gene into the immunoglobulin (Ig) heavy chain locus via gene targeting. This approach circumvents the isolation of the rearranged immunoglobulin variable genes from the tumor and the preparation of tumor-specific vector constructs. The low production of Id/GM-CSF fusion proteins by transfected cells, which is a major obstacle in the use of purified fusion proteins for immunotherapy, is due to the presence of the cytokine gene in the immunoglobulin locus. Low production, however, is not limiting in the cell-based setting, because upon in vivo administration of the modified autologous cells, even minute expression levels are sufficient to induce tumor immunity.