<p>This study aimed to evaluate the atrophic changes induced by <i>Helicobacter pylori</i> VacA and compare them with other forms of atrophic gastritis.A comprehensive histomorphological analysis and immunohistochemical evaluation were performed on 984 endoscopic gastric mucosal biopsy samples from patients with endoscopically confirmed atrophic gastritis. <i>H. pylori</i> primarily adheres to surface mucus cells, where it proliferates and produces the vacuolating cytotoxin VacA. The underlying mechanism involves VacA inducing the upward migration and compensatory proliferation of cells located in the deeper regions of gastric pits, the isthmus of gastric glands, and the neck mucous cells, ultimately leading to gastric atrophy. In this study, a comparative analysis was performed with autoimmune atrophy, degenerative denaturation atrophy, drug-induced atrophy, and non-specific atrophy. Both clinical and histological characteristics were evaluated, and pathological diagnostic criteria for mucosal atrophy were proposed for the first time. Of the 984 cases examined, <i>H. pylori</i>-induced atrophic gastritis was identified in 648 cases, accounting for 65.9% (648/984); autoimmune atrophy in 34 cases, representing 3.5% (34/984); degenerative denaturation atrophy in 59 cases, representing 6.0% (59/984); drug-induced atrophy in 72 cases, making up 7.3% (72/984); and non-specific atrophy in 171 cases, accounting for 17.4% (171/984). <i>H. pylori</i> infection was found to be associated with a high prevalence of infectious atrophy, accompanied by active epithelial cell proliferation, intraepithelial neoplasia, early changes in mucosa-associated lymphoid tissue lymphoma, and cell proliferation outside the lymphatic follicular mantle. The comparative analysis of gastric mucosal atrophy induced by <i>H. pylori</i> VacA, in comparison to other forms of atrophic gastritis, is crucial for understanding the pathogenesis of gastric cancer and improving management strategies for its prevention and progression.</p>