Background: A previous phase I/II study of RT-DeVIC for newly diagnosed, localized ENKL demonstrated promising efficacy (5y-overall survival [OS], 70%; 5y-progression-free survival [PFS], 63%; %CR, 77%) and manageable toxicity (G3 mucositis, 30%; G3 infection, 26%) (JCO 2009, 2012). RT-DeVIC has been included as a suggested treatment regimen in the NCCN guidelines since 2011. However, the outcomes in clinical practice (CP) and prognostic factors of RT-DeVIC are largely unknown. Methods: This cooperative study by hemato-oncologists and radiation oncologists in Japan (UMIN000015491) retrospectively analyzed data from patients (pts) with ENKL who were diagnosed between 2000 and 2013. Results: Data from 358 pts with ENKL of any stage were collected from 31 institutes. RT-DeVIC was the most common first-line therapy in pts with localized ENKL (168/256, 66%). The median dose of RT was 50 Gy. A two-thirds dose of DeVIC was selected in 82% of the pts. With a median follow-up of 5.1 yrs, the 5y-OS and PFS of RT-DeVIC in 168 pts were 71% and 61%, respectively. In 149 pts who were treated with RT-DeVIC in CP, 37% were age > 60 yrs, and 28% had elevated serum LDH levels. With a median follow-up of 4.9 yrs, the 5y-OS and PFS of 149 pts were 71% (95% CI, 62-78%) and 60% (95% CI, 51-68%), respectively. The %CR was 82%. There was no treatment-related death. G3/4 mucositis was recorded in 38% (G3, n = 53; G4, n = 2), and G3/4 infection occurred in 22% (G3, n = 30; G4, n = 1) of 144 evaluable pts who received RT-DeVIC in CP. These toxicities were transient and manageable. A multivariate analysis in 146 pts with localized ENKL who were treated with RT-DeVIC identified soluble interleukin-2 receptor (sIL-2R) > upper limit of normal (ULN) and ECOG PS > 1 as independent factors for worse OS. Of note, a multivariate analysis identified sIL-2R > ULN as the sole independent factor for worse PFS (HR, 3.46; P< .001). Conclusions: The efficacy and safety of RT-DeVIC was validated by the large number of pts in this study. Elevated pretreatment sIL-2R was associated with worse OS and PFS in pts with localized ENKL who received RT-DeVIC.