The efficiency of upfront consolidation with high-dose chemotherapy/autologous stem-cell transplantation (HDCT/ASCT) for newly diagnosed high-risk diffuse large B-cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high-risk DLBCL patients with age-adjusted International Prognostic Index (aaIPI) score 2 or 3. As induction chemotherapy, 6 cycles of R-CHOP-14 (arm A) or 3 cycles of R-CHOP-14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2-year progression-free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). A total of 71 patients were enrolled. With a median follow-up of 40.3 months, 2-year PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5-81.2%) and 66.7% (95% CI, 48.8-79.5%), respectively. Overall survival at 2 years in arms A and B were 74.3% (95% CI, 56.4-85.7%) and 83.3% (95% CI, 66.6-92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥3 non-hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R-CHOP-14 showed higher 2-year PFS and less toxicity compared with R-CHOP-14/CHASER in high-risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations. (UMIN-CTR, UMIN000003823).This article is protected by copyright. All rights reserved.