The impact of serum levels of soluble programmed cell death ligand 1 (sPD-L1) on prognosis in patients with Epstein-Barr virus-associated malignancies has never been investigated. We prospectively measured pre-and post-treatment serum sPD-L1 levels and evaluated their prognostic value in 97 patients with newly diagnosed, early stage extranodal NK/T-cell lymphoma (ENKTCL) treated with asparaginase-based chemotherapy followed by radiotherapy. For predicting survival outcomes, serum sPD-L1 levels of 3.23 ng/mL and 1.12 ng/mL were respectively identified for pre-and post-treatment cut-off levels. Patients with high pretreatment (> 3.23 ng/mL) had shorter progression-free survival (PFS) and overall survival (OS). In a multivariate survival analysis, post-treatment sPD-L1 > 1.12 ng/mL, treatment response (complete vs. non-complete response), and stage II disease were independent prognostic factors for shorter PFS and OS. In patients with a complete response, post-treatment sPD-L1 > 1.12 ng/mL was associated with shorter PFS and OS. In patients with high pretreatment sPD-L1 levels (> 3.23 ng/mL), low post-treatment sPD-L1 level (<= 1.12 ng/mL) correlated with longer PFS and OS. Our data suggest the post-treatment sPD-L1 level is a potent biomarker for predicting early relapse and poor prognosis in early stage ENKTCL patients treated with asparaginase, and may be a useful marker of minimal residual disease.