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CD19-targeted chimeric antigen receptor T-cell (CAR-T) immunotherapy has transformed the management of relapsed/refractory large B-cell lymphoma (LBCL), yet durable remissions are observed in less than half of treated patients. The tumor microenvironment (TME) is a key and understudied factor impacting CD19 CAR-T therapy outcomes. Using NanoString nCounter transcriptome profiling ( n  = 24) and multiplex immunohistochemistry (mIHC, n  = 15), we studied the TME in pretreatment biopsies from patients with LBCL undergoing CD19 CAR-T therapy. Patients who achieved complete response (CR) after CAR-T therapy demonstrated higher expression of genes associated with T-cell trafficking and function, whereas those who did not achieve CR had higher expression of genes associated with macrophages and T-cell dysfunction. Distinct patterns of immune infiltration and fibrosis in the TME were associated with CAR-T therapy outcomes, and these findings were corroborated using artificial intelligence-assisted image analyses. Patients who achieved CR had a lower proportion of the biopsy occupied by an interspersed immune infiltrate and a higher proportion of hypocellular/fibrotic regions. Furthermore, mIHC revealed lower density of CD4 + T cells and higher densities of both macrophages and tumor cells expressing PD-L1 in non-CR patients. Spatial analysis revealed that PD-1 + T cells were in close proximity to PD-L1 + macrophages or PD-L1 + tumor cells in patients who did not compared to those who did achieve CR after CAR-T therapy. These findings suggest that morphologic patterns in the TME and engagement of the PD-1/PD-L1 axis in pretreatment biopsies may impact CD19 CAR-T immunotherapy response in patients with LBCL., Competing Interests: Alexandre V. Hirayama has received research funding from Juno Therapeutics, a Bristol Myers Squibb Company, and Nektar Therapeutics; has received honoraria from Bristol Myers Squibb. Kimberly S. Smythe has received consulting/honoraria from Sensei Biotherapeutics. Salvatore Fiorenza reports grants from Bristol Myers Squibb and other support in the form of pending equity from Link Immunotherapeutics outside of the submitted work; has issued patents for PCT/US2021/025255 and PCT/US2021/025248d, and a patent for PCT/US2021/025260 issued, licensed, and with royalties paid from Bristol Myers Squibb. Jordan Gauthier has received research funding from Sobi, Juno Therapeutics, a Bristol Myers Squibb Company, Celgene, and Angiocrine Bioscience; has received consulting/honoraria from Sobi, Legend Biotech, Janssen, Kite Pharma, a Gilead company, and MorphoSys. Cecilia C. S. Yeung has received research funding from OBI, Lonza, Sensei, Signal One, and Pfizer; serves on scientific advisory boards for Twinstrand Biosciences, Abbvie, Eli Lily, and Loxo. David G. Maloney has received research funding from Juno Therapeutics, a Bristol Myers Squibb Company, Celgene, and Kite Pharma, a Gilead company; has served on ad hoc advisory board meetings from Amgen, BMS, Genentech, Gilead, Incyte, Janssen, Legend Biotech, Mustang Bio, MorphoSys, Novartis, Pharmacyclics, and Umoja; has rights to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics; serves on scientific advisory board with stock options and compensations for A2 Biotherapeutics and Navan Technologies. Cameron J. Turtle has received research funding from Juno Therapeutics, a Bristol Myers Squibb Company, NanoString Technologies, and Nektar Therapeutics; has served on scientific and consulting roles in the last 12 months for Caribou Biosciences, T‐CURX, Myeloid Therapeutics, ArsenalBio, Cargo Therapeutics, Differentia Bio, Advesya, eGlint, Celgene/Bristol Myers Squibb Cell Therapy, Novartis, Prescient Therapeutics, Century Therapeutics, IGM Biosciences, and Abbvie; serves on a DSMB for Kyverna; has stock options in Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, Cargo Therapeutics, and ArsenalBio; and has the right to receive payments from Fred Hutchinson Cancer Center as an inventor on patents related to CAR‐T cell therapy. The remaining authors have no conflicts of interest to report related to this work., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)