Over 30 years ago, the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was demonstrated to induce complete remissions and long-term disease-free survival in a considerable proportion of lymphoma patients. Since then many attempts to improve results by modifications of CHOP using escalated doses, additional drugs or the alternative use of putatively non-cross resistant chemotherapy regimens failed in randomized trials. While dose escalation strategies including high-dose approaches necessitating stem cell support have not yet unequivocally been demonstrated to be superior to a base-line CHOP-21, dose-dense bi-weekly modifications (CHOP-14) with growth factor support (G-CSF) improved the outcome of young and elderly patients with aggressive lymphomas compared to CHOP-21. A substantial improvement of treatment results has also been achieved by the implementation of rituximab into treatment protocols. Although not formally established in young patients with poor-prognosis, the combined immuno-chemotherapy with CHOP and rituximab has become an accepted standard for the treatment of diffuse large B-cell lymphoma (DLBCL) worldwide. For patients >60 years of age 6 courses CHOP-14 using G-CSF with rituximab (R-CHOP-14) followed by two additional courses of rituximab yielded the best treatment results without a relevant increase in toxicity compared with CHOP-21. For younger low-risk patients (aaIPI 0,1) 6 courses R-CHOP-21 are the standard treatment. Young high-risk patients (aaIPI ≥ 2) should be treated with dose-dense regimens within clinical trials.