Background: Diffuse large B-cell lymphoma (DLBCL); the commonest subtype of NHL, is genetically, biologically and clinically heterogeneous disorder which is potentially curable with combination chemo-immunotherapy, however, Prognostic assessment is important for tailoring therapy. Beclin-1, a mammalian ortholog of the yeast autophagy-related gene 6 protein, and important mediator of autophagy was found to predict clinical outcomes in many cancer patients. Methods: This prospective cohort study was carried out at medical oncology department, Zagazig University and Health insurance hospitals and included 32 patients with CD20 positive de novo DLBCL, they were subjected to routine clinical and laboratory assessment with immunohistochemical analysis for beclin-1 status which further divided the patients into 2 groups of high and low beclin-1,Patients received first line therapy with R-CHOP regimen, then assessed for therapy response and followed up after treatment for estimating overall (OS) and disease free survival (DFS). Results: High Beclin-1 expression was found in 12 patients (37.5%) and it wasn’t associated with significant correlation with clinic-demographic patient characteristics. The Complete remission rate was 59.4% and beclin-1 expression didn’t significantly affect clinical outcome, except for the significant death rate (p= 0.02). The 3-year OS and DFS were 78.1% and 45.0% respectively and high beclin-1 was significantly associated with better OS (by multivariate analysis) but not DFS. Conclusions: Beclin-1 didn’t provide a prognostic indicator for response to treatment. However, it's found to be independent predictor for OS in DLBCL patients.