Background: The Epstein-Barr virus (EBV) is involved in 40% of Hodgkin lymphoma (HL) cases; during latency, EBV produces epigenetic alteration in the host genome, decreasing the expression of the proapoptotic proteins and activating the expression of several survival immortalization genes. We aim to evaluate the expression of JAK/STAT and NF-kB pathways mRNAs and (PD-L1, Bcl-xL, and COX-2) as end-effect proteins and their correlation with clinicopathological and prognostic values in EBV positive and negative patients with classic Hodgkin lymphoma (CHL) Method: 64 patients between 2017 and 2022 with classic HL were classified into two groups; EBV positive and negative according to EBNA-1 detection by nested PCR. Expression levels of JAK/STAT and NF-kB pathways mRNA molecules (JAK2, STAT1, IRF-1, PD-L1, IFN-γ, NFkB, Bcl-xL, COX-2) by qRT-PCR, and the end-results proteins (PD-L1, Bcl-xL, and COX-2) by immunohistochemistry was evaluated and correlated with the clinicopathological and outcome parameters of both groups. The chi square test was used to analyses the expression levels and their relationships with clinic-pathological parameters, and the Kaplan–Meier method, for survival analysis. Results: Positive expression of mRNAs from both JAK/STAT and NF-kB pathways is highly significantly correlated with EBV-positive patients ( P<0.001). EBV-positive CHL patients were also were highly significantly associated with the end-results proteins (PD-L1, Bcl-xL, and COX-2) expression ( P<0.00) and with the presence of B-symptoms (p=0.022), presence of extranodal involvement (p=0.017), and advanced stage (p=0.018) respectively and were more susceptible to cancer progression and a higher incidence of relapse (p=0.008), poor disease free survival (DFS) (p=0.013), higher mortality (p=0.015) and low OS rates) p=0.028 ( Conclusion: EBV in CHL is associated with poor clinicopathological criteria, a higher incidence of disease progression, relapse, and worse overall survival through activating JAK/STAT and NF-kB signalling pathways.