Background and PurposeChimeric antigen receptor (CAR) T‐cell therapy is potentially associated with treatment‐related toxicities mainly consisting of cytokine release syndrome (CRS) and immune‐effector cell‐associated neurotoxicity syndrome (ICANS). We evaluated brain metabolic correlates of CRS with and without ICANS in diffuse large B‐cell lymphoma patients treated with CAR‐T.MethodsTwenty‐one refractory DLCBLs underwent whole‐body and brain [18F]‐fluorodeoxyglucose (FDG) PET before and 30 days after treatment with CAR‐T. Five patients did not develop inflammatory‐related side effects, 11 patients developed CRS, while in 5 patients CRS evolved in ICANS. Baseline and post‐CAR‐T brain FDG‐PET were compared with a local controls dataset to identify hypometabolic patterns both at single‐patient and group levels (p < .05 after correction for family‐wise error [FWE). Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were computed on baseline FDG‐PET and compared between patients’ subgroups (t‐test).ResultsICANS showed an extended and bilateral hypometabolic pattern mainly involving the orbitofrontal cortex, frontal dorsolateral cortex, and anterior cingulate (p < .003 FWE‐corrected). CRS without ICANS showed significant hypometabolism in less extended clusters mainly involving bilateral medial and lateral temporal lobes, posterior parietal lobes, anterior cingulate, and cerebellum (p < .002 FWE‐corrected). When compared, ICANS showed a more prominent hypometabolism in the orbitofrontal and frontal dorsolateral cortex in both hemispheres than CRS (p < .002 FWE‐corrected). Mean baseline MTV and TLG were significantly higher in ICANS than CRS (p < .02).ConclusionsPatients with ICANS are characterized by a frontolateral hypometabolic signature coherently with the hypothesis of ICANS as a predominant frontal syndrome and with the more prominent susceptibility of frontal lobes to cytokine‐induced inflammation.