Low concentrations of high-density lipoprotein cholesterol (HDL-C) have been reported in patients with hematological malignancies. However, the proof of decreased HDL-C in hematological malignancies and its association with clinical outcomes remain unclear. We analyzed 140 Japanese patients with malignant lymphoma (ML) and adult T-cell leukemia-lymphoma (ATLL). HDL-C, LDL-C and soluble interleukin-2 receptor (sIL-2R) were measured. Treatment decisions were determined with established protocols. HDL-C was 0.98 ± 0.45 mmol/l in patients and 1.51 ± 0.35 mmol/l in controls (P < 0.001). LDL-C was lower in patients than in controls (2.76 ± 0.96, 3.16 ± 0.76 mmol/l, respectively, P < 0.001). HDL-C was the lowest in ATLL (0.81 ± 0.37 mmol/l), modest in non-Hodgkin lymphoma (1.09 ± 0.42 mmol/l) and the highest in Hodgkin's disease (1.14 ± 0.68 mmol/l), (P = 0.0019). Inverse correlation was found between HDL-C and sIL-2R (r = −0.6584, P < 0.001). Categorized patients into 3 subgroups according to HDL-C (<0.52, 0.52–1.02 and ≥1.03 mmol/l), sIL-2R were the highest (median, 36,675; IQR, 17,180–92,600 U/mL) in patients with HDL-C < 0.52 mmol/l, modest (2386, 1324–8340) in HDL-C 0.52–1.02 mmol/l and the lowest (761, 450–1596) in HDL-C ≥ 1.03 mmol/l (P < 0.001). In Cox regression model, the lowest HDL-C levels, <0.52 mmol/l, were associated with poorer clinical outcome and the hazard ratio was 5.73 (95%CI, 3.09–10.50; P < 0.001). In Kaplan-Meier analysis according to HDL-C tertiles (<0.78, 0.78–1.10 and ≥1.11 mmol/l), patients with lowest HDL-C tertile showed inferior overall survival with a median follow-up of 23 months (P < 0.001). We concluded that cytokine-induced low levels of HDL-C in patients with ML and ATLL has independent prognostic significance, and suggesting an early indicator of poorer outcome.