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Gastrointestinal diffuse large B cell lymphoma (DLBCL) is a common subtype of extranodal lymphoma. There has been uncertainty about the clinical efficacy of combination therapy (surgery and chemotherapy) for gastrointestinal DLBCL. We retrospectively analyzed 114 patients with newly diagnosed gastrointestinal DLBCL from six medical centers. We evaluated four groups based on whether they were treated with or without surgery as the initial treatment for DLBCL, followed by either a regimen with cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) or CHOP with rituximab (R-CHOP). For all patients, treatment with R-CHOP resulted in significantly greater overall survival (OS; 93.2 vs 74.5 %, p = 0.008) and progression-free survival (89.8 % vs 72.7, p = 0.029). Tumor resection did not improve OS (84.0 vs 85.0 %, for surgery and chemotherapy alone, respectively, p = 0.980). However, for younger patients, overall survival was greater ( p = 0.005) for patients treated with surgery plus chemotherapy (83.9 %) than for patients treated with chemotherapy alone (40.0 %). Elevated serum lactate dehydrogenase level ( p = 0.004) and performance status (Eastern Cooperative Oncology Group; p = 0.003) were independent predictors of survival in patients with gastrointestinal DLBCL. Stage-modified IPI was recognized as the best prognostic tool. There were significant differences among patients with low-risk, intermediate-risk, and high-risk groups in 50-month OS (94.2 vs 84.0 vs 66.7 %, p = 0.008). The results of this large-scale study suggest that R-CHOP regimen is the first-line treatment for gastrointestinal DLBCL. The benefit of surgery for these patients remains controversial. Further prospective analyses are warranted. [ABSTRACT FROM AUTHOR]