[show abstract][hide abstract] ABSTRACT: Background: More aggressive treatment approaches (MACOP-B or consolidation with high dose therapy and autologous stem cell transplantation) have been considered superior to CHOP in primary mediastinal large B-cell lymphoma (PMLBCL). Rituximab-CHOP (R-CHOP) is the standard of care for diffuse large B-cell lymphoma, whereas efficacy in PMLBCL has not been adequately confirmed. Patient and Methods: Seventy-six (76) consecutive PMBCL patients who received R-CHOP±radiotherapy (RT) were compared to 45 consecutive historical controls treated with CHOP±RT. Baseline characteristics of both groups were balanced. Results: Early treatment failures were greatly reduced with R-CHOP±RT (9% vs. 27%; p=0.02). The 3-year freedom from progression (FFP) rate after R-CHOP±RT was 81% vs 50% for CHOP±RT (p=0.0002); 3-year event free survival (EFS) was 80% vs 49% (p=0.0002); 3-year overall (OS) and lymphoma specific survival (LSS) was 89% vs 67% (p=0.004) and 90% vs 67% (p=0.002) accordingly, with only 7/76 lymphomarelated deaths. Among R-CHOP responders, 52/68 received RT. Conclusions: Based on these results, most patients with PMLBCL appear to be cured by R-CHOP in 21-day cycles with or without RT, which could be the current standard of care. Therefore, the need for more aggressive treatment strategies is questionable. Further studies are required to establish the precise role of RT.