Background: CD5+ DLBCL is characterized by a poor prognosis and frequent central nervous system (CNS) relapse after standard immunochemotherapy. In the primary analysis of our multicenter phase II study of DA-EPOCH-R/HD-MTX for newly diagnosed stage II-IV CD5+ DLBCL, the 2-year (yr) progression-free survival (PFS) was 79% and the 2-yr CNS relapse rate was 9% at a median follow-up of 3.1 yrs (Miyazaki, et al. 2020). The aim of this preplanned 5-yr follow-up was to assess PFS, overall survival (OS), the CNS relapse rate, and late toxicity. Methods: A total of 47 patients (pts) with newly diagnosed stage II-IV CD5+ DLBCL between 20-75 yrs old and ECOG PS of 0-3 were enrolled. The treatment included 4 cycles of DA-EPOCH-R followed by 2 cycles of HD-MTX (3.5 g/m²) and 4 additional cycles of DA-EPOCH-R. Intrathecal administration of MTX and/or cytarabine was not allowed. 45 (96%) pts completed the protocol treatment. The data were updated as of December 1, 2020. Results: The median follow-up of alive pts was 6.0 yrs (range, 5.0-7.7). The pts’ characteristics were as follows: age, 37-74 yrs (median, 62); male, 38%; ECOG PS > 1, 4%; stage III/IV, 57%; IPI HI/H, 47%; CNS-IPI high, 21%; and ABC/GCB/unclassified (n = 46), 85%/9%/7%. The 5-yr PFS and OS were 72% (95% CI, 57-83%) and 79% (95% CI, 64-88%), respectively. The 5-yr PFS and OS of pts with CD5+ ABC DLBCL (n = 39) were 72% and 74%, respectively. The 5-yr CNS relapse rate in all 47 pts was 9% (95% CI, 3-22%). There were no CNS relapse events after the primary analysis. Neither grade 3/4 late adverse events nor cardiac events of any grade were observed. Possible second malignancies were recorded in 6 (13%) pts. Among them, one pt who received R-ICE as salvage therapy experienced acute myeloid leukemia. The other 2 pts had colon cancers treated with endoscopic polypectomy/mucosal resection. Conclusions: Both the survival benefit and safety of DA-EPOCH-R/HD-MTX were maintained during a 5-yr follow-up, indicating the excellent efficacy, and safety of this approach as a first-line therapy for CD5+ DLBCL. Clinical trial information: UMIN000008507.