Objectives: The aim of this review was to compare the efficacy of asparaginase (ASP)-containing vs ASP-absent regimens in the first-line treatment of ENKTL patients. Methods: The PRISMA protocol was used to search PubMed and Embase for both controlled and uncontrolled studies of ASP or alternative chemotherapy (CT) for newly diagnosed ENKTL, published in English by March 2017. The regimens were compared to calculate relative risk (RR) with 95% confidence interval (CI) of the overall response rate (ORR), complete response (CR) or partial response (PR). Results: Out of 38 studies included, eight were controlled trials, with the pooled RR of ORR in stage I-II 1.54 (95% CI 1.34–1.77); stage I-IV 1.34 (95% CI 1.09–1.64). In stage III-IV CT combined with radiotherapy (RT), RR of ORR was 2.30 (95% CI 1.66–3.18). ASP was also superior in achieving CR. When all single arms combined, RR of ORR after CT with ASP was 1.52 (95% CI 1.38–1.67) in stage I-II (15 studies); 1.44 (95% CI 1.32–1.57) in all stages (29 studies); 1.31 (95% CI 1.24–1.38) and 1.66 (95% CI 1.18–2.34) in stages I-II and III-IV combined with RT, correspondingly. Conclusions: ASP-based CT significantly improved ORR and CR in patients with newly diagnosed both early-stage and advanced-stage ENKTL. © 2017 Informa UK Limited, trading as Taylor & Francis Group.