AbstractLow-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach, gastric MALT lymphoma, is associated with Helicobacter pylori infection. The eradication of H pylori using antibiotics is successful in 60% to 80% of affected patients. In contrast to the previous paradigm, we and other investigators have shown that a certain proportion of patients with H pylori–positive early-stage diffuse large B-cell lymphoma (DLBCL) of the stomach with histological evidence of MALT lymphoma, including high-grade transformed gastric MALT lymphoma and gastric DLBCL(MALT), achieved long-term complete pathological remission (pCR) after first-line H pylori eradication therapy, indicating that the loss of H pylori dependence and high-grade transformation are separate events in the progression of gastric lymphoma. In addition, patients with H pylori–positive gastric DLBCL without histological evidence of MALT (gastric pure DLBCL) may also respond to H pylori eradication therapy. A long-term follow-up study showed that patients who achieved pCR remained lymphoma free. Gastric MALT lymphoma is indirectly influenced by H pylori infection through T-cell stimulation, and recent studies have shown that H pylori–triggering chemokines and their receptors, H pylori–associated epigenetic changes, H pylori–regulated miRNA expression, and tumor infiltration by CD4+CD25+ regulatory T cells contribute to lymphomagenesis of gastric MALT lymphoma. Recent studies have also demonstrated that the translocation of CagA into B lymphocytes inhibits apoptosis through p53 accumulation, BAD phosphorylation, and the up-regulation of Bcl-2 and Bcl-XL expression. In gastric MALT lymphoma, CagA may stimulate lymphomagenesis directly, through the regulation of signal transduction, and intracellular CagA is associated with H pylori dependence. These findings represent a substantial paradigm shift compared with the classical theory of H pylori–reactive T cells contributing indirectly to the development of MALT lymphoma. In conclusion, a wide range of H pylori–related gastric lymphomas have been identified. The use of antibiotics as the sole first-line therapy for early-stage gastric pure DLBCL requires validation in a prospective study. The clinical and biological significance of the CagA oncoprotein in the lymphomagenesis of gastric MALT lymphoma warrants further study.