Background: Approximately 25% of all pts with localized nasal ENKL experience disease progression during the first two years (yrs) after diagnosis under new treatments including concurrent chemoradiotherapy. The clinical features of those pts are largely unknown. Methods: The database of our study (NKEA project; UMIN000015491) was used for the present analysis. Data from pts with newly diagnosed localized (stage IE and contiguous IIE) nasal ENKL diagnosed between 2000 and 2013 at 31 institutes in Japan and treated with RT-DeVIC were retrospectively analyzed. Progression of disease within 2 yrs (POD24) (Casulo, JCO 2015) was applied as the definition of early progression. Results: Of 162 pts, 38 were in the POD24 group (23%) and 124 were in the reference group. Treatment yrs and doses of RT and DeVIC were not associated with the incidence of POD24. With a median follow-up of 5.8 yrs, the overall survival (OS) of the POD24 group was inferior to that of the reference group (P< 0.00001; 2-yr OS, 26% vs. 100%; 5-yr OS, 23% vs. 89%). The POD24 group showed the following features more frequently than the reference group: serum soluble interleukin-2 receptor (sIL-2R) level > upper limit of normal (ULN) (25/33, 76%; P = 0.000012), C-reactive protein (CRP) > ULN (28/37, 76%; P = 0.013), and detectable Epstein-Barr virus (EBV)-DNA in peripheral blood (15/17, 88%; P = 0.033). The positive predictive value and negative predictive value of elevated sIL-2R for POD24 were 42% and 90%, respectively; those of elevated CRP were 31% and 87%, respectively; and those of detectable EBV-DNA were 39% and 90%, respectively. Of the 9 pts who were negative for all three factors, none experienced POD24. A multivariate analysis in the POD24 group identified elevated sIL-2R as an independent predictive factor for worse OS (HR 3.16; 95% CI, 1.07 - 9.32). Conclusions: Pretreatment sIL-2R, CRP, and EBV-DNA were associated with POD24 among pts with localized nasal ENKL treated with RT-DeVIC. The strong association of elevated sIL-2R with early progression and short OS in the POD24 group provides a rationale for targeting strategies.