Cyclophosphamide, doxorubicin, vincristine, and prednisone, given every 3 weeks (CHOP-21), is standard chemotherapy for aggressive lymphomas. To determine whether biweekly CHOP (CHOP-14) with or without etoposide is more effective than CHOP-21, 689 patients ages 61 to 75 years were randomized to 6 cycles of CHOP-21, CHOP-14, CHOEP-21 (CHOP plus etoposide 100 mg/m2 days 1-3), or CHOEP-14. Patients in the 2-weekly regimens received granulocyte colony-stimulating factor (G-CSF) starting from day 4. Patients received radiotherapy (36 Gy) to sites of initial bulky disease and extranodal disease. Complete remission rates were 60.1% (CHOP-21), 70.0% (CHOEP-21), 76.1% (CHOP-14), and 71.6% (CHOEP-14). Five-year event-free and overall survival rates were 32.5% and 40.6%, respectively, for CHOP-21 and 43.8% and 53.3%, respectively, for CHOP-14. In a multivariate analysis, the relative risk reduction was 0.66 (P =.003) for event-free and 0.58 (P <.001) for overall survival after CHOP-14 compared with CHOP-21. Toxicity of CHOP-14 and CHOP-21 was similar, but CHOEP-21 and in particular CHOEP-14 were more toxic. Due to its favorable efficacy and toxicity profile, CHOP-14 should be considered the new standard chemotherapy regimen for patients ages 60 or older with aggressive lymphoma.