Background: Stomach hemorrhage and perforation are very severe and com-mon complications in patients with primary gastric diffuse large B -cell lym-phoma (PG-DLBCL) during treatment with immunochemotherapy. However, no relevant clinical studies have been performed on the prevention of these serious complications.Methods: Patients diagnosed with PG- DLBCL were enrolled in this retrospective study. The prevention group received standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R- CHOP) treatment without prednisone combined with antacids and anti-Helicobacter pylori (Hp) therapy. These patients received R- CHOP- based treatment until the complete recovery of gastric ulcers, as proven by gastroscopy. The control group received a standard R- CHOP regimen. Toxicity and survival were the main endpoints.Results: A total of 52 patients received preventative treatment, while 146 patients did not. Among patients with stage I, II -1, and II -2 disease, the prevention group had a lower rate of hemorrhage and perforation (0/40) than the control group (10/78, p = 0.044). At a median follow- up time of 25 months, the 5- year event- free survival (EFS) rates were 97.1% in the prevention group and 66.1% in the control group (p = 0.025), and the 5- year overall survival (OS) rates were 100% and 72.0%, respectively (p = 0.021). However, the differences in the 5- year EFS and OS of patients with disseminated disease were not statistically significant.Conclusions: Preventative treatment can decrease the risk of hemorrhage and perforation in patients with localized PG- DLBCL during immunochemotherapy, leading to better EFS and OS in these patients. However, preventative treatment failed to reduce the risk of gastric hemorrhage and perforation and did not im-prove survival (EFS and OS) in advanced- stage patients.