No standard chemotherapy regimens have been defined yet for extranodal natural killer/T cell lymphoma (ENKTL), and the prognosis of patients with advanced or relapsed disease is very poor. Daratumumab, an investigated anti-cancer drug targeting CD38, has been of great interest in the treatment of CD38-expressing malignancies, especially multiple myeloma. In this study, we reviewed the clinical data of 94 patients with ENKTL, investigated the expression of CD38, and analyzed the prognostic value of CD38 expression. Forty-seven patients had weak expression of CD38, and the other 47 patients had strong expression. The complete response (CR) rate was significantly higher in patients who were treated with asparaginase-based therapy (83.8 vs. 59.6 %, p = 0.025). There was a trend towards higher CR rate in CD38 weak expression group (78.7 vs. 59.6 %, p = 0.074). At a median follow-up time of 42 months, the 2-year and 5-year progression-free survival (PFS) rates were 53.0 and 39.0 %, respectively, and the 2-year and 5-year overall survival (OS) rates were 68.0 and 58.0 %, respectively. In multivariate survival analysis including CD38 expression status, International Prognostic Index (IPI) score, local tumor invasion, and chemotherapy regimens, it was found that strong expression of CD38 and non-asparaginase-based chemoregimens were independent adverse prognostic factors for PFS (p = 0.009 and 0.027, respectively), while local tumor invasion and higher IPI score were independent adverse prognostic factors for OS (p = 0.002 and 0.035, respectively). In subgroup analysis, strong expression of CD38 significantly correlated with inferior survival outcomes in patients without local tumor invasion (p = 0.011) or with stage I-II disease (p = 0.008). In conclusion, we firstly found that the majority of ENKTL cases were CD38 positive, with half had strong expression of CD38, which significantly correlated with poor outcomes, indicating the potential role of CD38 as a therapy target for ENKTL.