Randomized controlled trials have studied different dose-intensity and dose-interval regimens of R-CHOP for patients with diffuse large B-cell lymphoma (DLBCL). This study was undertaken to confirm these results in a population-based setting, with special emphasis on the value of 6xR-CHOP21 among patients aged 18–64 years. Two thousand three hundred and thirty-eight stage II–IV DLBCL patients, ≥18 years, we confirmed the similar efficacy of six versus eight cycles of R-CHOP and of R-CHOP21 versus R-CHOP14 regimens across all age groups on overall survival (median follow-up 36.4 (1.3–167.6) months). Nevertheless, overall survival decreased with older age. Interestingly, in patients 18–64 years, the adjusted risk of mortality among recipients of 6xR-CHOP21 compared to other R-CHOP regimens seems to be similar (HR 0.62; 95%CI: 0.38–1.02; p= .059). Although this finding might suggest that 6xR-CHOP21 could be considered as first-line regimen for all stage II–IV DLBCL patients, it should be confirmed in forthcoming population-based studies with larger patient numbers and longitudinal follow-up.