Studies have found that lymphoma patients often exhibit abnormal lipid metabolism, and a decrease in serum high-density lipoprotein cholesterol (HDL-C) may occur during lymphomagenesis and tumor growth. However, no literatures have investigated the role of HDL-C in patients with extranodal natural killer/T cell lymphoma (ENKTL). In this study, we retrospectively reviewed the HDL-C level in 107 patients newly diagnosed with ENKTL that received either l-asparaginase-based regimen or EPOCH regimen as induction chemotherapy, and evaluated its prognostic value. The mean level of HDL-C was 1.10 mmol/L (range, 0.15-2.63), and the HDL-C level was significantly lower in patients with elevated LDH and beta 2-microglobulin (beta 2-MG) (p = 0.017 and 0.001, respectively) and those who underwent disease progression and died (p = 0.031 and 0.007, respectively). In univariate survival analysis, higher Eastern Cooperative Oncology Group performance status score (a parts per thousand yen1), Ann Arbor stage III-IV, elevated LDH, higher international prognostic index (IPI) score (a parts per thousand yen2 vs. 1 vs. 0), decreased HDL-C level (< 40 mg/dL), elevated beta 2-MG level, and response status after induction chemotherapy correlated significantly with poor progression-free survival (PFS) and overall survival (OS) (p < 0.05). In a multivariate Cox regression model that included IPI score, HDL-C level, beta 2-MG level, and response status after induction chemotherapy, it was found that HDL-C level and response status after chemotherapy were independent prognostic factors for OS (p = 0.014 and 0.010, respectively) and PFS (p = 0.016 and 0.020, respectively). In conclusion, HDL-C was found to be a valuable independent prognostic factor in ENKTL, and the mechanism needs to be further investigated, which may offer the possibility of therapeutic targets.