The optimal therapy for primary mediastinal B-cell lymphoma is a subject of ongoing debate, with no accepted standard of care. We performed a retrospective analysis of 63 patients in the modern era treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), with or without radiation. Median age was 37 years (range 20-82). Eighty percent had limited stage disease and 71% were bulky. By age-adjusted International Prognostic Index (IPI), 15% were low-risk, 52% low-intermediate, 27% high-intermediate and 6% high-risk. Some 77% of responding patients received consolidative radiotherapy. Overall and complete response rates were 79% and 71%. Primary induction failure occurred in 13 (21%) patients. Five-year PFS and OS were 68% and 79%, respectively. Adverse prognostic features included increased IPI, advanced stage, advanced age and multiple extranodal sites. These data demonstrate an unacceptably high rate of primary refractory disease on R-CHOP, particularly among patients with high-risk features. Novel treatment approaches are needed that reduce primary refractory disease and reliance on mediastinal radiation in young people.