Background. Muscle depletion (MD) assessed by computed tomography (CT) has been shown to be a predictive marker in solid tumors, but has not been assessed in non-Hodgkin’s lymphomas. Despite software improvements, MD measurement remains highly time-consuming and cannot be used in clinical practice. Methods. This study reports the development of a Deep-Learning automatic segmentation algorithm (DLASA) to measure MD, and investigate its predictive value in a cohort of 656 diffuse large B cell lymphoma (DLBCL) patients included in the GAINED phase III prospective trial (NCT01659099). Results. After training on a series of 190 patients, the DLASA achieved a Dice coefficient of 0.97 ± 0.03. In the cohort, the median skeletal muscle index was 50.2 cm2/m2 and median muscle attenuation (MA) was 36.1 Hounsfield units (HU). No impact of sarcopenia was found on either progression free survival (PFS) or overall survival (OS). Muscular hypodensity, defined as MA below the tenth percentile according to sex, was associated with a lower OS and PFS, respectively (HR = 2.80 (95% CI 1.58–4.95), p < 0.001, and HR = 2.22 (95% CI 1.43–3.45), p < 0.001). Muscular hypodensity appears to be an independent risk factor for mortality in DLBCL and because of DLASA can be estimated in routine practice.