Objective: To explore the clinical efficacy and safety of rituximab combined with chemotherapy and single chemotherapy for diffuse large B cell lymphoma (DLBCL). Methods: A total of 97 patients with DLBCL were selected. Patients treated by single chemotherapy were designed as control group, while those by rituximab combined with chemotherapy as observational group. All patients were treated for at least 4 cycles. The short-term and long-term efficacy and related adverse reactions of 2 groups were observed. Results: The rate of complete remission (CR) in observational group was significantly higher than in control group (χ²=4.6589, P=0.0309). However, there was no significant difference in objective remission rate (ORR) between 2 groups (P=0.3651). The rates of 3-year overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) were 80.30% (53/66), 69.70% (46/66) and 59.09% (39/66) in observational group, and 61.29% (19/31), 58.06% (18/31) and 58.06% (18/31) in control group, respectively. The OS in observational group was significantly longer than in control group (P=0.035). However, there was no significant difference in PFS, DFS and rate adverse reactions between 2 groups (P=0.089; P=0.438; χ²=0.1562, P=0.6927). Conclusion: Rituximab combined with chemotherapy can improve the efficacy of DLBCL without increasing the adverse reactions, which can be used as the first-line treatment for DLBCL, thus deserving to be widely applied in clinic.