Granulocyte-macrophage colony stimulating factor (GM-CSF) has been associated with multiple immune effects, which could enhance the outcome of chemotherapy. For this reason we decided to explore the combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) given every 14 days with pegfilgrastim (Neulasta) and GM-CSF (Leukine). A total of 59 HIV-negative patients with aggressive-histology non-Hodgkin lymphoma were accrued. The median age was 56 years (range 25-87). Lactate dehydrogenase (LDH) was high in 36 patients (61%); performance status was 0-1 in 48 patients; International Prognostic Index (IPI) was 0-1 in 30 and 2-3 in 24 patients; and disease was stage I-II in 46% and III-IV in 56% of patients. Diffuse large B-cell lymphoma was the most common lymphoma type. Response rates were: complete remission (CR) in 51 (86%), partial remission (PR) in five (8%) and failure in three patients (5%). At a median follow-up of 26 months, the overall survival (OS) at 3 years was 76% and the 3-year failure-free survival (FFS) was 73%. No patient relapsed beyond 18 months. Patients with IPI ≥ 3 had a 3-year progression-free survival (PFS) of 54% versus 82% in those with IPI < 3 (p = 0.038). Patients aged < 60 years had a FFS of 77% while those aged ≥ 60 years had a FFS of 69% (p = 0.29). Both the CR rate and the quality of CRs were satisfactory, with only 5/51 (10%) of complete responders having lost their remissions to date. Of interest is that age ≥ 60, an important adverse prognostic factor, appeared to have lost some of its importance, since the difference between those aged < 60 and ≥ 60 years was minimal in our study. The results with R-CHOP-GM-CSF every 14 days are encouraging, and merit a prospective comparative clinical trial against R-CHOP-14 in order to elucidate the contribution of GM-CSF.