Primary mediastinal B-cell lymphoma (PMBL) is often cured with dose-dense anthracycline-based regimens but the prognosis at relapse or progression remains poor. While anti-CD19 CAR-T cell therapy has dramatically improved outcomes in relapsed or refractory large B-cell lymphoma, far less is known about their efficacy in PMBL. Using the systematic record of all patients treated with CAR-T cells prospectively included in the DESCAR-T registry in France, along with centrally reviewed positon-emission tomography (PET) imaging, we describe the outcomes and key determinants of treatment success in PMBL patients treated over a 6-year period. Among 82 patients infused in the registry we observed a best complete response (CR) rate, 2-year progression-free survival (PFS), and 2-year overall survival (OS) of 68.1%, 57.4%, and 73.8%, respectively. Outcomes were even better for the 62 patients infused with axicabtagene ciloleucel, with best CR rate, 2-year PFS, and 2-year OS reaching 74.5%, 70.4%, and 86.9%, respectively. Achieving a Deauville score of 1-4 or a ΔSUVmax reduction of more than 24% at the 1-month evaluation was associated with excellent outcomes, whereas increased total metabolic tumor volume baseline PET increased the risk of treatment failure. Surprisingly, neither the response to bridging therapy nor the type of bridging therapy (chemotherapy versus immune checkpoint inhibitors) were associated with long-term outcomes. In conclusion, this study confirms that anti-CD19 CAR-T cells as a valid standard-of-care for relapsed and refractory PMBL and highlights key determinants of treatment success.