Background: More research is ongoing on obesity as a risk factor for cancer occurrence. Cell of origin (COO), stage and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) are frequently used for risk evaluation and treatment tailoring in patients with Diffuse large B-cell lymphoma (DLBCL). Relatively, few studies assessed the prognostic role of obesity and leptin level in patients with DLBCL. Aim: The aim of this study was to investigate the effect of obesity and leptin level on response and prognosis in DLBCL. Methods: A single institution prospective study that included patients with DLBCL. For each patient, demographic data, body mass index (BMI), serum leptin level by ELISA, response and survival were determined. Results: Seventeen (24.3%) out of the 70 patients in our cohort were classified as obese (BMI>30). They had a higher serum leptin level (p < 0.001) and less response to R-CHOP chemotherapy (P= 0.003). Forty (57.14%) patients had elevated serum leptin level with B symptoms, Cell of origin and response to chemotherapy were significantly different between the two groups. There was no significant relationship between BMI and survival. On the other hand, higher serum leptin was associated with worse disease-free survival (p=0.035). Conclusion: The results support a relationship between both BMI and serum leptin level and response to treatment in DLBCL patients. Leptin level like other common prognostic factors is related to disease-free survival.