Background:The aim of this study was to investigate the prognostic role of mammalian target of Rapamycin (mTOR) andC-X-C chemokine receptor type 4 (CXCR4) in diffuse large-B-cell lymphoma (DLBCL) patients.Patients and methods:This retrospective study was collected data from 64 de novo DLBCL patients, who received standardizedR-CHOP therapy at two oncology centers. CXCR4 and mTOR expressions were assessed by immunohistochemistry.Results:Out of the 64 DLBCL patients, 40 patients were positive for CXCR4 (62.5%) and 35 patients for mTOR (54.7%)expressions. CXCR4 expression was positively correlated with mTOR expression (r = 0.7;p< .001). While mTOR expressionwas significantly associated with high lactate dehydrogenase level (p= .03) and number of extranodal sites one or more (p=.02), CXCR4 expression was significantly associated with high IPI score (p< .001) and ECOG PS (p= .005). Furthermore, theexpression levels of mTOR and CXCR4 were significantly associated with older ages and poor response to treatment (p= .04,< .001and .04, .03, respectively). After a median Follow up of 22 months, mean±SD overall survival (OS) was 65.391±4.705.Kaplan–Meier analysis showed that patients positive for mTOR and CXCR4 expression had shorter DFS (p= .01 & .02) andOS (p= .02 & .04). Multivariate analysis showed that CXCR4 and mTOR positivity is an independent prognostic factor forsignificantly poorer DFS (p= .03, and .02 respectively) but not for OS (p= .09 and .08 respectively) in the DLBCL pateints.Conclusion:Our results indicate that the expression of CXCR4 and mTOR may be poor prognostic biomarkers in DLBCL