There are currently no prognostic biomarkers for extranodal natural killer/T-cell lymphoma (ENKTL) patients receiving asparaginase-based chemotherapy. Interleukin-10 (IL-10) is a pleiotropic cytokine that is involved in the stimulation and suppression of immune responses and influences the prognosis of different subtypes of lymphoma. We retrospectively analyzed 98 newly diagnosed patients with ENKTL receiving asparaginase-based chemotherapy. Baseline serum IL-10 levels were tested with sandwich enzyme-linked immunosorbent assays. Patients with high IL-10 (>= 12.28 pg/mL) at diagnosis tended to have more adverse clinical features. Patients with low IL-10 (<12.28 pg/mL) at diagnosis had better progression-free survival (PFS) (P<0.001) and overall survival (OS) (P<0.001). Multivariate analysis revealed that baseline serum IL-10 level >= 12.28 pg/mL, stage III/IV, elevated serum ferritin, and elevated serum Epstein-Barr virus DNA level at diagnosis were four adverse factors for PFS and OS. Based on these four independent prediction factors, we divided the patients into different subgroups as follows: group 1, no adverse factors; group 2, one factor; group 3, two factors; and group 4, three or four factors. Furthermore, significant differences in PFS and OS were found between the groups. Our results suggest that pretreatment serum IL-10 is a novel, powerful predictor of prognosis for ENKTL patients receiving asparaginase-based chemotherapy, which suggests a role for IL-10 in the pathogenesis of this disease and offers new insight into potential therapeutic strategies.