The purpose of this study was to evaluate the CNOP regimen (cyclophosphamide, mitoxantrone, vincristine, and prednisone) throughout a community based oncology network with a large number of elderly non-Hodgkin's lymphoma (NHL) patients. Three hundred and seventy-three previously untreated patients with diffuse aggressive NHL received the CNOP regimen administered through a community oncology network, the Nebraska Lymphoma Study Group (NLSG). The complete response rate was 60% with an overall response rate of 73%. The estimated 4-year event-free survival for patients <60years was 44%, compared to 38% for those >age 60 (p = 0.18). However, the 4-year estimated overall survival for patients <60 years was 62% compared to 44% for those >60 years (p < 0.001). Prognostic factors predictive for a poor event-free survival were male gender, stage III/IV disease, Karnofsky score <80, and elevated lactic dehydrogenase (LDH). The lymphoma specific cumulative death rate was 29% for patients <60 years compared with 33% for patients >60 years (p = 0.07). After failing CNOP the 4-year overall survival (OS) was 19%. The estimated 4-year OS for patients who failed CNOP and went on to receive high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplant (ASCT) was 64% for patients < age 60 and 48% for those >60 years (p = 0.23). In conclusion, CNOP chemotherapy administered to patients with diffuse aggressive NHL in a community oncology network produces similar result to that reported for other anthracycline based regimens reported in the literature. Patients >age 60 had a higher rate of failure due to causes other than lymphoma which accounted for a worse survival long-term. However, patients of all ages who failed CNOP and who were able to receive HDC and ASCT demonstrated long-term disease survival after the transplant.