Objective: Diffuse-large-B-cell-lymphoma (DLBCL) can complicate B-cell-primary-immunodeficiencies (PIDs) course or induce total gamma-globulin level (TGL) lowering, whose clinical status as an effective secondary immunodeficiency (SID) remains unspecified. This study aims to assess the frequency, clinical and prognostic relevance of the lowest TGLs discovered at DLBCL diagnosis. Results: In a two year monocentric retrospective cohort, 96 patients diagnosed with DLBCL who had a serum electrophoresis (SEP) were included. Patients were divided into the lowest (L)- and the highest (H)-TGLs (TGL ≤5.5 g/L and TGL >5.5 g/L) subgroups and compared for outcomes, including fatal infectious events. In our cohort, 12 (12.5%; 8 males; median age: 68 [55—82] years) exhibited L-TGL. There was no differences regarding demographics, Ann-Arbor-lymphoma-stages, inflammatory parameters or chemotherapy regimen between both groups. However, overall (10/12, 83.3% versus 22/96, 26.2%; p=0.03) and infection-related death rates (10/12, 83% versus 6/96, 6.2%; p<0.001) were significantly higher in the L-TGL group. Conclusion: We demonstrate for the first time the strong negative impact of L-TGL on overall and infection-related mortality in DLBCL. Prospective studies should distinguish DLBCL-related SIDs from preexisting humoral PIDs, using biomolecular testing and post-treatment TGLs monitoring to determine the best management strategy for infectious risk during DLBCL treatment in L-TGL context.