Aim of the work: This is a prospective double blind randomized phase II study evaluating biweekly CHOP with G-CSF vs. CHOP+Etoposide q 21 days .The primary end points were response rate, toxicity profile. The secondary end points were time to treatment failure and two years actuarial survival. In addition, evaluation of serum TNF, IL-6, and tissue BCL-2, MDR overexpression were assessed for their prognostic significance and their correlation with treatment outcome in the two treatment arms.Patients and methods: Between March 2003 and March 2005, 40 patients with newly diagnosed aggressive NHL aged 18 to 65 years, , and Ann Arbor stages II - IV were enrolled into the study , each treatemnt arm consists of 20 patients. Measurement of serum levels of TNF alpha and IL-6 were done by ELISA, measurement of Bcl-2 , MDR , were done by using quantitative RT- PCR on fresh lymph node biopsies .Results: In the arm 1 (CHOP-14 ) , the median age of patients was 47.5 years, compared to 65 years in the arm 2 (CHOEP ). Stage II represented 35 % of cases and advanced stages (III & IV ) represented 65 % in the arm 1 , while 60 % of patients in the arm 2 had stage II , and 40 % had an advanced stage. 65 % of patients achieved CR, 25 % PR vs. 75 % ,15 % in the arm 1 and 2 respectively . . In the CHOEP arm , infections grade 3 was present in 50 % of patients vs. 10 % in the CHOP-14 arm, p=0.006. In the Univariate analysis , in the arm 1, IL-6 has a statistically significant impact on both the response and the overall survival. TNF was the strongest independent factor predicting the overall survival, while MDR and BCL-2 have an impact on the response only. The actuarial estimate of DFS at 2 years was 60 % vs. 78 % for the arm 1 , and arm 2 respectively , P=0.2 . The actuarial estimate of OAS at 2 1/2 years was 57 % vs. 78 % for the arm 1 , and arm 2 respectively , P=0.3.Conclusion: The overall response rate for CHOP-14 and CHOEP was similar for both treatment regimens . The actuarial estimate of DFS and OAS were better for the CHOEP arm , however with no statistical significance . The toxicity profile was similar in both treatment regimens , with only infections grade 3 being higher in the CHOEP arm (p=0.006 ) Elevated levels of Serum TNF alpha , IL-6, overexpression of tissue MDR , and BCL-2 could be used to define high risk patients, however ,due to small number of patients , it is difficult to draw firm conclusions regarding their impact on treatment outcome.