BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition often triggered by malignancies, especially T/NK-cell lymphoma-associated HLH (T/NK-LAHLH). Epstein-Barr virus (EBV) infection is strongly linked to T/NK-LAHLH and worsens prognosis. However, the prognostic value of whole-blood EBV DNA levels in T/NK-LAHLH remains unclear, necessitating further investigation to improve risk assessment and treatment strategies. OBJECTIVE: To investigate the clinical characteristics and prognostic significance of whole-blood EBV DNA status in patients with T/NK-LAHLH. DESIGN: A single-center, retrospective study was conducted, including 85 patients diagnosed with T/NK-LAHLH between January 2017 and August 2022. Patients were categorized based on EBV DNA status, and clinical outcomes were compared. METHODS: EBV DNA levels were quantified using polymerase chain reaction (PCR) assays. Kaplan-Meier survival and Cox regression models to assess overall survival (OS) and identify independent prognostic factors. RESULTS: A total of 85 T/NK-LAHLH patients were included, with a median age of 52 years (range: 18-81 years) and 60% male. The OS rates at 1, 3, 6, and 12 months were 66.6%, 49.8%, 33.8%, and 28.4%, respectively. Among these patients, 67 (78.8%) were EBV DNA-positive, while 18 (21.2%) were EBV DNA negative. EBV DNA-positive patients exhibited significantly lower platelet and globulin levels, higher IL-10 levels, and prolonged activated partial thromboplastin time compared to EBV DNA-negative patients ( CONCLUSION: Whole-blood EBV DNA positivity is a significant prognostic factor for poor outcomes in T/NK-LAHLH patients. These findings highlight the need for incorporating EBV DNA monitoring into clinical management and further research to refine therapeutic strategies.