Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin lymphoma. High total metabolic tumor volume (TMTV) calculated using 18 F-FDG PET/CT images at diagnosis predicts poor prognosis of patients with DLBCL. However, high cost and poor access to the imaging facilities hamper wider use of 18 F-FDG PET/CT. In order to explore a surrogate marker for TMTV, we evaluated the correlation between the serum levels of soluble interleukin-2 receptor (sIL-2R) and TMTV in 64 patients with DLBCL, and the results were verified in an independent validation cohort of 86 patients. Serum levels of sIL-2R were significantly correlated with TMTV. ROC analysis revealed that the cutoff value of TMTV ≥150 cm3 or sIL-2R ≥ 1300 U/mL could predict failure to achieve EFS24 with areas under the curve (AUC) 0.706 and 0.758, respectively. Each of TMTV ≥150 cm3 and sIL-2R ≥1300 U/mL was significantly associated with worse 5-year overall survival and event-free survival. Importantly, each of sIL-2R <1300 U/mL or TMTV <150 cm3 identified patients with favorable prognosis among NCCN-IPI high-intermediate and high-risk group. Serum level of sIL-2R represents a convenient surrogate marker to estimate metabolic tumor burden measured by 18 F-FDG PET/CT that can predict treatment outcomes of patients with DLBCL. © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.