The prognosis of patients with stage III/IV NK/T-cell lymphoma (NTCL) is extremely poor. Although L-asparaginase (L-asp) is effective for NTCL, its significance has not been clearly demonstrated. In addition, there are few studies comparing treatment outcomes in stage III/IV NTCL. This study evaluated the efficacy of L-asp-based chemotherapy and prognostic factors in stage III/IV NTCL. Seventy patients with newly diagnosed stage III/IV NTCL were enrolled between January 2000 and February 2013. Patients received ifosfamide, etoposide, methotrexate, and prednisolone (IMEP) plus L-asp (N = 22) or combination chemotherapy without L-asp (N = 48) as a first-line treatment. Clinical prognostic factors, treatment outcomes, and prognostic scores were compared between the groups. After a median follow-up period of 12.8 months (range, 1.1-186.6 months), median overall survival (OS) and progression-free survival (PFS) were 11.3 and 5.6 months, respectively. Treatment outcomes were superior in patients treated with IMEP plus L-asp compared to those treated with chemotherapy without L-asp (overall response rate, 90.0 vs. 34.8 %, P < 0.001; complete remission rate, 65.0 vs. 21.7 %, P = 0.001). The OS and PFS were significantly higher for the IMEP plus L-asp group compared with the chemotherapy without L-asp group. In a multivariate analysis, the use of chemotherapy without L-asp was an independent predictor of reduced OS (hazards ratio (HR) = 2.18, 95 % confidence interval (CI) 1.08-4.40; P = 0.030) and PFS (HR = 2.29, 95 % CI 1.22-4.29; P = 0.010). IMEP plus L-asp is active against stage III/IV NTCL, and it is an independent predictor of improved survival.