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Background: Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma. European guidelines recommend FDG-PET/CT for staging and end of treatment (EOT) response assessment, mid-treatment response assessment is optional. We compared the Lugano classification and PET Response Criteria In Solid Tumours (PERCIST) for FDG-PET/CT response assessment in DLBCL head-to-head., Methods: We retrospectively included patients with DLBCL who underwent first-line R-CHOP(-like) therapy (2013-2020). Interim and EOT FDG-PET/CT response were reevaluated using the Lugano classification and PERCIST. Response was dichotomized into complete metabolic response (CMR) versus non-CMR (interim and EOT) and responders versus nonresponders (interim only). The cutoff for nonresponse at interim was a Deauville score of 5 (DS5) with the Lugano classification and a partial metabolic response with ≤66% reduction in SUL peak using PERCIST (PERCIST66)., Results: In multivariable Cox regression (N = 170), DS5 at interim, PERCIST66 at interim, non-CMR at EOT with the Lugano classification and non-CMR at EOT with PERCIST were predictive of progression-free survival (PFS). The Lugano classification and PERCIST agreed perfectly at interim and EOT and with 98.4% for the identification of nonresponders at interim. The accuracy for predicting events within 2 years of diagnosis was 84.2% for DS-5 at interim, 87.6% for PERCIST66 at interim, 86% for non-CMR with the Lugano classification at EOT and 83.3% for non-CMR with PERCIST at EOT., Conclusion: The Lugano classification and PERCIST were equally predictive of PFS. Nonresponse at interim and non-CMR at EOT were predictive of poor PFS with comparable accuracy for predicting events within 2 years., (© 2023 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)