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Upper aerodigestive tract natural killer (NK)/T-cell lymphoma (UNKTL) is the most common type of extranodal NK/T-cell lymphoma, nasal type. Serum beta2-microglobulin (β2-M) was found to be a predictor in some subtypes of B-cell lymphoma. However, its prognostic significance in NK/T-cell lymphoma has never been explored. We retrospectively analyzed 82 patients newly diagnosed as UNKTL. Serum β2-M was detected prior to treatment in this series. Various statistical analyses were performed to evaluate the significance of the relevant clinical parameters. High serum β2-M level was calculated as ≥2.5 mg/L by the median value. The number of patients with serum β2-M ≥2.5 mg/L at diagnosis was 39 (47.6%) and 43 patients (52.4%) with β2-M <2.5 mg/L. Patients with high serum β2-M level at diagnosis seemed to have more adverse clinical features: B symptoms ( p = 0.007) and elevated LDH level ( p < 0.001), and high KPI score ( p = 0.002). Serum β2-M ≥2.5 mg/L was significantly associated with poor overall survival (5-year OS, 35.2% vs 73.6%; p = 0.001) and progression-free survival (5-year PFS, 27.5% vs 55.9%; p = 0.028). For patients with early stage, serum β2-M at diagnosis could also help to distinguish those with favorable outcomes from those with poor outcomes. In multivariate analysis, high serum β2-M level remained its prognostic impact on survival (OS: p = 0.002; PFS: p = 0.039), independent of the International Prognostic Index score. Our study suggested high serum β2-M was a novel predictor of prognosis in patients with UNKTL. A simply and regular way might be established to identify UNKTL patients of different risks at diagnosis. [ABSTRACT FROM AUTHOR]