Introduction: Follicular lymphoma (FL) usually presents an indolent course with repeated events of disease progression but treatment-free time intervals and patients’ survival are reduced at each relapse. Many prognostic scores exist but few are used in practice due to their complexity. Total metabolic tumor volume (TMTV) has demonstrated a strong prognostic value in FL and its routine use is increasing in academic centers. We aim to explore the predictive value of a simple prognostic score based on TMTV and beta-2-microglobulin (B2M) levels at baseline in high tumor burden FL to identify patients with the highest unmet medical need. Methods: In this monocentric retrospective analysis, we enrolled adult patients admitted to our hospital between 2006 and 2018 and fulfilling the following inclusion criteria: grade 1 to 3A FL with at least one high tumor burden criteria defined by the Groupe d'Etude des Lymphomes Folliculaires (GELF), available PET-CT images collected before first-line standard immunochemotherapy start and suitable for TMTV assessment. Baseline TMTV was determined using the 41% SUVmax threshold method. B2M levels were routinely measured at diagnosis. Primary endpoints were progression-free survival (PFS) and overall survival (OS) according to a score combining TMTV and B2M. Results: We included 126 FL patients in this analysis. Median age at time of treatment was 61 years (55; 57). Patients displayed advanced-stage disease (n = 112, 88.9%), intermediate (n = 51, 40.8%) or high (n = 62, 49.6%) FLIPI and intermediate (n = 40, 33.3%) or high (n = 31, 25.8%) PRIMA-PI scores. Median baseline SUVmax and TMTV were 12.1 (10; 17) and 606 mm3 (268;1219), respectively. Baseline B2M levels were measured for 125 (97%) patients and >3 mg/L in 30 (24%). Treatment regimens used were mostly R-CHOP like (n = 109, 86.5%) and R-lenalidomide (n = 9, 7.1%). 80 patients (63.5%) received a maintenance therapy during 24 months. We defined three risk categories : (i) Low risk (n = 45, 36%): TMTV ≤510 mm3 and B2M ≤3 mg/L; (ii) Intermediate risk (n = 57, 45.6%) : TMTV >510 mm3 or B2M >3 mg/L ; (iii) High risk (n = 23, 18.4%) : TMTV >510 mm3 and B2M >3 mg/L. With a median follow-up of 83 (52; 116) months, the 5-year PFS was 81.7% (95% CI: 71–94), 53.7% (95% CI: 41.8–69) and 38.6% (95% CI: 23–65) in the low, intermediate and high risk groups, respectively (p < 0.0001). Five-year OS was based on 14 deaths and estimated at 96.1% (95% CI: 91–100), 89.1% (95% CI: 81.2–97.7) and 73.7% (95% CI: 57.6–94.2) in the low, intermediate and high risk groups, respectively (p = 0.003). Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, PET-CT No conflicts of interests pertinent to the abstract.