BACKGROUND: This study was designed to assess the activity and safety of dose-adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with rituximab (DA-POCH-R) in elderly patients with poor-prognostic untreated diffuse large B-cell non-Hodgkin lymphoma (DLBCL). METHODS: From April 2006 to November 2009, 23 patients, aged !70 years, with an age-adjusted International Prognostic Index (IPI) of 2 or 3, were enrolled. Only patients with left ventricular ejection fraction (LVEF) !50% were allowed. The DA-POCH-R regimen was administered every 3 weeks for a minimum of 6 and a maximum of 8 cycles. RESULTS: Median patient age was 77 years (range, 70-90 years); 83% of patients had Ann Arbor stage III to IV disease. Median LVEF at baseline was 62%. Four (17%) patients had a history of abnormal cardiovascular conditions. Twenty-one (91%) patients were evaluable for response. The overall response rate was 90%, with a complete response rate of 57%. The 3-year overall survival and event-free survival rates were 56% and 54%, respectively. Neutropenia (48%) was the most frequent grade 3 to 4 adverse event (AE); no grade 3 to 4 cardiac AEs were observed. CONCLUSIONS: DA-POCH-R was an active and safe combination therapy for patients aged !70 years with poor-prognostic untreated DLBCL. This regimen was a reasonable alternative for elderly patients who were not considered to tolerate standard R-CHOP treatment. Cancer 2011;117:964-73.