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Objective To investigate the histomorphological characteristics of the gastric mucosa and the prognosis in patients with Helicobacter pylori infection. Methods Progressive damage to the gastric mucosa was examined by immunohistochemistry in 2294 patients with H. pylori infection and follow-up information was analyzed. Results H. pylori initially colonized the mucus layer covered by the gastric mucosa epithelium, then selectively adhered to and destroyed the surface mucus cells causing intra-gastric and extra-gastric lesions. Gastric mucosal damage induced by H. pylori was divided into five stages according to the depth of H. pylori invasion and degree of lesion deterioration: mucilaginous, surface mucocellular, lamina propria lesion, mucosal atrophy, and intraepithelial neoplasia stages. Morphological follow-up analysis revealed no significant difference in 6-month curative effects between stage I and stage II, but significant differences were found between stages II and III, stages III and IV, and between stages IV and stage V, respectively. Conclusions This novel staging strategy may be a valuable tool for diagnosing and predicting the results of gastric mucosal damage induced by H. pylori infection.