Introduction: Central nervous system (CNS) involvement in patients with refractory or relapsed large B-cell lymphoma (LBCL) is associated with an extremely poor prognosis. Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an approved treatment for patients with refractory or relapsed (R/R) LBCL that has changed the prognosis of patients with chemoresistant LBCL. However, data regarding efficacy and safety of CART cell treatment in patients with active CNS involvement are limited since they are excluded from most of clinical trials. Methods: We retrospectively collected data from 75 patients with LBCL, treated with CART cells from January 2020 to January 2023 in Henri Mondor Hospital. We identified 13 patients with active CNS involvement at the time of CAR-T cell treatment decision: 12/13 had abnormal neurological examination, 8/11 had head and/or medullar MRI abnormalities consistent with lymphoma and 9/10 had detectable lymphoma cells in the cerebrospinal fluid. We compared the characteristics of the 13 patients with CNS involvement (CNS+) with 62 patients without evidence of active CNS disease (CNS-). Median age was 69 and 59 years, respectively (p = 0.05). CNS+ patients received a median of 2 previous lines of treatment versus 3 for CNS- patients (p = 0.34). Performance status prior to CART-cell injection was 2 or more in 9/13 (69%) and 11/62 (18%) p < 0.001, respectively. 5/13 (38%) CNS+ patients had high grade B-cell lymphomas versus 11/62 (18%) CNS- (p = 0.13). CAR-T-cell was axi-cel in 10/13 (77%) CNS+ patients versus 42/62 (68%) CNS– (p = 0.74). It is noteworthy that 7/13 (54%) CNS+ patients had pre-existing low-grade B-cell lymphomas versus 15/62 (24%) CNS- (p = 0.046). Results: The best overall response rate was identical in both groups: 12/13 (92%) in CNS+ patients versus 51/61 (92%) in CNS-, including 11/13 (85%) and 44/61(72%) complete metabolic response. As shown in the figure, median progression free survival and overall survival was 5.5 and 8.4 months, respectively in CNS+ patients versus 11.5 and 21 months in CNS- patients (not significant). Regarding safety, 13/13 (100%) CNS+ patients had a cytokine release syndrome (10 grade 1–2 and 3 grade 3) versus 54/62 (87%) CNS- (49 grade 1–2 and 5 grade 3–4) and 10/13 (77%) experienced ICANS (6 grade 1–2 and 4 grade 3–4) versus 28/62 (45%) CNS- (27 grade 1–2 and 1 grade 3–4) (p = 0.06 and 0.02 for grade 3–4). Transfer into an intensive care unit occurred in 4/13 (31%) CNS+ patients versus 9/62 (15%) CNS- (p = 022). Median time of hospitalization was 37 days for CNS+ patients versus 20 days for CNS- patients (p = 0.007). Six CNS+ patients died from which 5 died of progression and 1 of infection. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Immunotherapy Conflicts of interests pertinent to the abstract. F. Lemonnier Consultant or advisory role: BMS, Kiowa, Miltenyi Educational grants: Gilead, Janssen, Roche L. Roulin Educational grants: Kite gilead, Novartis, Bristol myers squibb