Primary gastric mucosa-associated lymphoid tissue (MALT) lymphoma may develop from chronic infection with Helicobacter sp. in the mouse model. The mechanisms of pathogenesis remain unclear. Regulation of B-cell proliferation and death are important features to investigate. Proteins encoded by bcl-2 family genes, e.g., Bcl-XL, regulate apoptosis; and alterations in the expression of these genes can contribute to the development of cancer. Our aim was to determine the role of Bcl-XL in B lymphocytes in the development of gastric MALT lymphoma associated with Helicobacter infection using the BALB/c mouse model. We analyzed 37 animals with Helicobacter-associated MALT (n = 25), low-grade MALT lymphoma (n = 10) and high-grade lymphoma (n = 2), investigating the in vivo distribution of Bcl-XL in B cells/B-lymphoma cells using immunohistochemical analysis. In vitro cultivation of B cells/B-lymphoma cells was employed to perform RT-PCR analysis of Bcl-XL mRNA expression after cell stimulation with Helicobacter antigen. We found significant Bcl-XL protein expression in B lymphocytes within MALT and low-grade MALT lymphoma, whereas there was no and minimal expression, respectively, of Bcl-XL in the 2 high-grade MALT lymphoma cases. Expression of bcl-XL mRNA in B lymphocytes was up-regulated in vitro upon Helicobacter-antigen stimulation and associated with prolonged cell survival. These findings support the hypothesis that Bcl-XL plays a role in the pathogenesis of B-cell MALT lymphoma by providing cell-survival signals and by triggering the acquisition of MALT. © 2001 Wiley-Liss, Inc.