(1) Background: CAR-T-cell therapy is a novel therapeutic option for patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). The parameters that predict a favorable outcome after CAR-T-cell treatment are a matter of ongoing exploration. (2) Methods: We analyzed 36 consecutive patients with r/r DLBCL receiving tisagenlecleucel or axicabtagene ciloleucel at a single academic institution. We hypothesized that lymphoma subtypes (transformed versus de novo DLBCL) are of

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... c importance. We also assessed age, previous treatment, bridging therapy, remission status at the time of CAR-T treatment and at six months, LDH, the occurrence of CRS or ICANS, and CAR-T-DNA ddPCR kinetics for their prognostic impact. (3) Results: CRS was observed in 24 (67%) patients, and ICANS was observed in 14 (39%) patients. CR was achieved in 20 (56%) patients. Achievement of CR within six months after CAR-T was associated with better PFS (p < 0.0001) and OS (p < 0.0001). Remarkably, transformed (=secondary) lymphoma was associated with a better outcome than de novo disease for PFS (p = 0.0093) and OS (p = 0.0209), and the CR rate was 78% versus 33% (p = 0.0176). Mortality in patients with transformed DLBCL was 23% compared with 56% in de novo patients (p = 0.0209). (4) Conclusion: The presence of transformed DLBCL seems to be associated with a more favorable course after CAR-T treatment than that observed in the de novo DLBCL patients.