Study outline and results. Fecal 16S rRNA, shotgun metagenomic sequencing, and serum multiplex enzyme-linked immunosorbent assay (ELISA) were performed in a large cohort of newly diagnosed patients with DLBCL who were treated with RCHOP and in healthy individuals. Patients with DLBCL exhibit a profound dysbiosis, marked by high Enterobacteriaceae overrepresentation relative to short-chain fatty acid–producing bacteria. High relative abundance of Enterobacteriaceae in patients with DLBCL was associated with higher interleukin 6 (IL-6) and interferon gamma (IFN-γ) plasmatic concentrations, increased risk of febrile neutropenia, and lower PFS, compared with patients with no dominance of Enterobacteriaceae family members.