Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T-or NK-cell lymphoproliferative diseases. It is a disease with poor outcome. Almost all current therapies are ineffective except of allogeneic hematopoietic stem cell transplantation.We investigated the efficacy and safety of programmed death 1 (PD-1) blockade (Sintilimab), combined with lenalidomide, which is an immunomodulatory drug, in an open-label, single-center, prospective study involving CAEBV patients. PD1 blockade 2mg/kg was given every two weeks by intravenous infusion on day 1, and lenalidomide 5mg (age<18 years)/10mg (age>=18 years) was given orally once a day on day 1-14.As of Nov 15, 2020, 34 patients were enrolled. As of the Feb 1, 2021 analysis cut-off date, 24 cases completed at least 3 courses and were assessed for efficacy. The overall response rate is 54.2% (13/24, 45.8% complete response; 8.3% partial response). EBV-DNA copies in PBMC decreased significantly (p=0.002). The proportion of CD8+T cells in lymphocytes increased (p=0.007). The comparative analysis between response group and non-response group showed the proportion of Effector Memory CD8+ T cells and cytokines of CTLs activation (IFN-γ, CD27, CD30, MIG, IP-10) increased significantly in Response-group after treatment. Whole-exome sequencing generated from peripheral blood and saliva samples reveal that Non-Response group had a higher somatic mutational load of copy number variation in background. With a median follow-up time of 17.8 months, 22 of 24 patients were alive with an estimated survival probability of 91.3% at 1 year. All 34 patients were assessed for safety evaluation. The possible drug-related adverse events were reported in 17 (50%) patients.PD-1 blockade combined with lenalidomide was an effective and safe therapy for CAEBV patients. The significant therapeutic effect and the different characteristics between response and non-response group, provides a possible predictive value for CAEBV treatment option.Copyright © 2023. Published by Elsevier Ltd.