BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive lymphoma. Rituximab-based conventional chemotherapy still leads to drug resistance or relapse in 30-40% of patients. Therefore, early identification of high-risk patients and accurate assessment of prognosis are very important for clinical decision-making. The aim of this study is to investigate the value of F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) of tumor metabolic, clinical and biological parameters in the prognostic risk stratification of DLBCL before treatment. METHODS: We retrospectively collected clinical data on 63 patients with newly diagnosed DLBCL admitted to Shanxi Bethune Hospital during the period from November 2016 to April 2020 who underwent F-FDG PET/CT prior to treatment in a cohort study. Metabolic, clinical, and biological parameters were analyzed by Cox regression. Kaplan-Meier curves of patient survival were compared by the log-rank test. RESULTS: The median follow-up was 21 months. The 2-year progression-free survival (PFS) was 47.62%, and the overall survival (OS) was 53.97%. The subtype, double expression, Ann Abor stage, NCCN-IPI score, Ki-67, maximum standardized uptake value (SUV), bulk volume glycolysis (BVG), total lesion glycolysis (TLG), total metabolic tumor volume (TMTV) were the influencing factors for PFS and OS (P<0.050) in univariate analysis. BVG (PFS: HR =6.62, P<0.001; OS: HR =3.53, P=0.029), TLG (PFS: HR =8.56, P<0.001; OS: HR =5.20, P=0.004), TMTV (PFS: HR =12.02, P=0.001; OS: HR =5.05, P=0.033) and Ki-67 were found to be independent prognostic risk stratification parameters affecting PFS and OS by multivariate regression analysis. The 2-year PFS and OS rates for patients with high BVG (≥288.00 cm), TLG (≥1,854.00 cm), TMTV (≥103.00 cm), and Ki-67 (≥85%) were 20% and 28.57%, 9.68% and 22.58%, 20.51%, and 30.77%, and 25% and 33.33%, respectively; and the 2-year PFS and OS rates for patients with low BVG (<288.00 cm), TLG (<1,854.00 cm), TMTV (<103.00 cm), and Ki-67 (<85%) patients were 82.14% and 85.71%, 84.37% and 84.37%, 91.67% and 91.67%, and 61.54% and 66.67%, respectively. Patients with high BVG, TLG, TMTV, and Ki-67 had a worse 2-year PFS as well as OS rate (Ki-67: P=0.0018/P=0.0025; P<0.0001 for the rest of the groups). CONCLUSIONS: Our findings suggest that BVG, TLG, TMTV, and Ki-67 are independent prognostic indicators for survival in patients with pre-treatment DLBCL, especially BVG, which is a novel prognostic indicator that has to be validated in future research.