Mucosa-associated lymphoid tissue (MALT) B-cell lymphomas develop in the context of autoimmune or chronic inflammations like Helicobacter pylori-induced gastritis. Remission of most gastric MALT lymphomas after eradication of H pylori links tumor cell proliferation to antigen-induced inflammation and the need for antigenic contact. Furthermore, the tumor cells correspond to antigen-activated memory B cells. To investigate the reactivity of the tumor immunoglobulins we employed in vitro-generated antibodies identical to those produced by MALT lymphoma cells. The immunoglobulin rearrangements of 7 MALT lymphomas were amplified, cloned, and expressed as single-chain fragment variable (scFv) antibodies. Antigen specificity of these 7 scFvs was analyzed by immunohistochemical staining of various normal, reactive, and malignant human tissues. Also, an expression library comprising approximately 30,000 proteins from human fetal brains (protein filter) and a peptide library were screened. One scFv stained a subpopulation of tonsillar plasma cells in immunohistochemical studies. On protein filters this scFv recognized the plasma cell-related protein Ufc1. Peptide library screening identified 9 peptides as binding partners of an additional scFv. The majority of MALT lymphoma immunoglobulins studied, however, showed no reactivity against antigens, indicating that the tumor immunoglobulins do not play a significant role in stimulation and proliferation of the MALT lymphoma tumor cells.