Introduction: Classical Hodgkin Lymphoma (CHL) is characterized by PD-L1/L2 deregulation with the effectiveness of PD-1 blockage treatment. Pre-treatment level of soluble PD-L1 (sPD-L1) was more elevated in diffuse large B-cell lymphoma (DLBCL) patients than in controls and was associated with overall survival. We evaluated pre-treatment sPD-L1 level of 126 CHL patients included in a prospective study of the Lymphoma Study Association (LYSA) and 37 controls. Methods: The cohort consisted in 126 CHL patients enrolled between 1998 and 2002 in a prospective study of the LYSA assessing the prognostic values of plasma cytokines and soluble receptors. A peripheral blood sample for plasma was collected from all patients at diagnosis before any treatment. The protein expression of sPD-L1 was evaluated in duplicate using an ELISA kit. A Zero-Inflated Binomial-Negative regression model was used to compare sPD-L1 levels in CHL patients and controls. Correlation between log-transformed sPD-L1 level and clinical characteristics, EBV status and cytokine levels measured before any treatment (IL-10, TNFα, TNF-R1, TNF-R2, IL-6, IL-1Rα, sCD30), response to initial treatment and progression-free survival (PFS) were investigated. Results: the median age of the 126 CHL patients was 33 years (range, 15-93), 68% had an Ann Arbor stage I-II and 71% had an IPS score of 0-2. Nodular sclerosis was the main histologic subtype (83%). The EBV status was positive in 18 (27%) patients. 67% patients were treated with ABVD, 14% of patients progressed or relapsed and 11% died. sPD-L1 mean level in CHL patients was 3.56 times more elevated in cases than in controls (95% CI: 2.66-4.76, p= 8.2e-13; estimated means for cases and controls: 869 vs 3093 pg/ml; medians: 549 vs 1954 pg/ml). No statistically significant correlation/association was found between sPD-L1 level and age, Ann Arbor stage, ECOG-PS, IPS, lymphocyte count, EBV status, the different evaluated cytokines, response to treatment and PFS. Conclusions: CHL patients have a PD-L1 level in plasma which is higher than controls and DLBCL patients. Further studies are needed to decipher the prognostic role of sPD-L1 level in larger cohort including patients with more advanced stages and treated with immune checkpoint inhibitors.