The role of extranodal (EN) sites as potential sanctuary regions resistant to CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in large B-cell lymphoma (LBCL) remains unclear. To investigate this, we retrospectively analyzed 283 adults treated with commercial CD19 CAR-T therapy, assessing 958 PET-CT scans across four time points: pre-apheresis, pre-lymphodepletion, best response, and relapse. EN involvement prior to CAR-T therapy was common (76%). Outcomes for patients with exclusive EN disease were similar to those with nodal (ND) disease alone; however, patients with concomitant EN and ND disease (EN + ND) had lower complete response rates and shorter progression-free survival. Site-specific outcomes varied: lungs/pleura/pericardium and gastrointestinal/peritoneum involvement had the lowest local response rates (48% and 51%, respectively). Notably, the risk of same-site relapse was highest in the lungs/pleura/pericardium (hazard ratio [HR] 7.8) and gastrointestinal/peritoneum (HR 5.97). Among patients relapsing after CAR-T, two-year overall survival rates from time of relapse were significantly lower in those with EN relapse (23% for exclusive EN; 25% for EN + ND) compared to exclusive ND relapse (64%; p = 0.008). These findings underscore the high prevalence of EN disease in CAR-T recipients and its site-specific impact on outcomes, highlighting the need for organ-targeted strategies to enhance treatment efficacy. Differential site-specific response and relapse/progression risk according to pre-CAR-T therapy anatomical site involvement in Large B-cell Lymphoma. Risk of site-specific relapse or progression was not evaluable for CNS/orbital/cranial sinuses, adrenal/genitourinary, hepatobiliary/pancreas, and spleen due to insufficient number of events.