Background: Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) is a common subtype of extranodal non-Hodgkin lymphoma (NHL), with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) as the commonly used treatment regimen. However, full cycles of standard R-CHOP present the risk of severe bleeding or perforation, even leading to emergency surgery, especially for those with deep lesions in their first 1-2 cycles of treatment. This study aims to explore the safety and efficacy of fractioned R-CHOP (rituximab d0, 50% dose of CHOP d1 and d5) followed by standard R-CHOP cycles in PG-DLBCL patients guided by endoscopic ultrasonography (EUS). Patients and Methods: Thirty-one PG-DLBCL patients were analyzed in this retrospective study. All patients had lesions infiltrated to at least the 3rd layer of the stomach under EUS at baseline. Patients switched to standard R-CHOP if they showed the reduced infiltrated layers and restricted lesions after fractioned R-CHOP cycles. Results: The overall response rate, 5-year progression-free survival (PFS) and overall survival (OS) of patients in our study were 93.5%, 75% and 84%, respectively. No treatment delay or dosage reduction from gastric adverse event was observed. None of the patients in our study suffered from severe bleeding or perforation during the treatment. Kaplan-Meier analyses showed that PG-DLBCL patients characterized by multiple localization, lesions ≥3cm, having B symptoms, lower serum albumin level, and elevated LDH level were associated with worse PFS and OS. Conclusion: Our data indicate that it might be an effective approach in treating deeply infiltrated PG-DLBCL patients by switching fractioned R-CHOP to standard R-CHOP cycles guided by EUS.