Background and Purpose: The ability of autologous hematopoietic stem cell transplantation (ASCT) to improve the benefit of patients with high-risk diffuse large B-cell lymphoma (DLBCL) who achieved complete remission (CR) following induction chemotherapy is controversial. This multicenter real-world study aimed to explore the efficacy and safety of the rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen followed by consolidated ASCT therapy in newly diagnosed DLBCL. Methods: From June 2018 to June 2021, the clinical data of patients with high-risk DLBCL who reached CR after receiving the R-CHOP regimen from ten lymphoma diagnosis and treatment centers were analyzed. Patients were included in the R-CHOP+ASCT (with consolidated ASCT therapy, n = 60) and R-CHOP (follow-up without consolidated ASCT therapy, n = 60) groups. The efficacy in the two groups was compared by difference analysis, and the safety of R-CHOP+ASCT was analyzed. Results: Until June 2024, the median follow-up times for the R-CHOP+ASCT and R-CHOP groups were 44 (37.25-56) and 43.5 (38-52) months, respectively. Survivors were followed up for at least 36 months. In the R-CHOP+ASCT group, the 3-year disease-free survival (DFS) and overall survival (OS) rates were 89.7% and 96.7% and those in the R-CHOP group were 63.9% and 85.9%, respectively. The 3-year DFS rate in the R-CHOP+ASCT group was significantly higher than that in the R-CHOP group (89.7% vs 63.9%, P = 0.001); no significant difference was found in the 3-year OS rate between the R-CHOP+ASCT and R-CHOP groups (96.7% vs 85.9%, P = 0.113). The 5-year DFS and OS rates in the R-CHOP+ASCT group were 73.6% and 77.6% and those in the R-CHOP group were 56.5% and 81.1%, respectively. The 5-year DFS rate in the R-CHOP+ASCT group was significantly higher than that in the R-CHOP group (73.6% vs 56.5%, P = 0.009), whereas no significant difference was found in the 5-year OS rate between the R-CHOP+ASCT and R-CHOP groups (77.6% vs 81.1%, P = 0.246). In the Cox multifactorial analysis, discontinuous consolidated ASCT therapy, bone marrow invasion, and dual expression were poor prognostic factors that affect DFS [hazard ratio (HR), 5.710; 95% confidence interval (CI), 2.241-14.548, P < 0.001; HR, 4.324; 95% CI, 1.890-9.893, P = 0.001; HR, 2.565; 95% CI, 1.145-5.747, P = 0.022, respectively] and dual expression was a poor prognostic factor for OS (HR, 3.486; 95% CI, 1.300-9.344, P = 0.013). Grade IV myelosuppression after transplantation developed in the R-CHOP+ASCT group, and other common grade 3 or 4 treatment-related adverse events were infection and fever. Conclusion: For patients with newly diagnosed high-risk DLBCL, consolidated ASCT therapy can increase the DFS rate of those with CR status following the R-CHOP regimen, and the safety is controllable.