Extranodal natural killer/T cell lymphomas, nasal type (ENKLs), which are a group of non-Hodgkin lymphomas with poor prognoses, are much more common in China than in Western countries. Here, we retrospectively assessed the impact of two treatment regimens on clinical response and survival among 42 ENKL patients. All patients were diagnosed with stage IV, relapsed, or refractory ENKL. Twenty patients received modified SMILE (consisting of L-asparaginase, methotrexate, ifosphamide, etoposide, and dexamethasone) chemotherapy, and 22 control patients received CHOP (consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone) treatment. Higher complete response (CR) and overall response rates (ORR) (CR 45.0 vs. 13%, ORR 70 vs. 36%) were observed among the patients treated with the modified SMILE regimen (Fisher's exact = 0.040, Pearson χ(2) P = 0.030). Similarly, a higher ORR rate was observed among Epstein-Barr virus-positive patients (ORR 50.0 vs. 18.0%, Fisher's exact = 0.049). The treatment group was also significantly associated with longer overall survival (OS) and progression-free survival (PFS) (Log-rank, P = 0.0341, P = 0.0142, respectively), but OS did not seem to be longer. Treatment-related toxicity was monitored in all patients throughout the protocol. There were no significant differences in the incidence of hematological and non-hematological toxicities between the two groups (P < 0.05), with the exception of peripheral neuropathy (treatment = 0 control = 5, Fisher's exact = 0.049).