Purpose: Etoposide to standard R-CHOP is used for high-risk diffuse large B-cell lymphoma (DLBCL) in some countries. Due to the lack of randomized trials, a real-world data study using matching methods was used to test the potential effectiveness of R-CHOEP over R-CHOP. Patients and Methods: This study included patients from the Danish Lymphoma Register diagnosed between 2006 and 2020 at the age of 18–60 years with de novo DLBCL and age-adjusted IPI ≥2. R-CHOEP treated patients were matched 1:1 without replacement to R-CHOP treated patients using a hybrid exact and genetic matching technique. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: In total, 396 patients were included; 213 received R-CHOEP and 183 received R-CHOP. Unadjusted 5-year PFS and OS for R-CHOEP were 69% (95% Confidence intervals [CI]; 63%–76%) and 79% (CI;73%–85%) versus 62% (CI;55%–70%) and 76% (CI;69%–82%) for R-CHOP (log-rank test, PFS p =.25 and OS p =.31). A total of 127 patients treated with R-CHOEP were matched to 127 patients treated with R-CHOP. Matching-adjusted 5-year PFS and OS were 65% (CI; 57%–74%) and 79% (CI; 72%–84%) for R-CHOEP versus 63% (CI; 55%–73%) and 79% (CI;72%–87%) for R-CHOP (log-rank test, PFS p =.90 and OS p =.63). Conclusion: The present study did not confirm superiority of R-CHOEP over R-CHOP for young patients with high-risk DLBCL.