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Abstract Infection has emerged as the chief cause of non‐relapse mortality (NRM) post CD19‐targeting chimeric antigen receptor T‐cell therapy (CAR‐T) therapy. Even though up to 50% of patients may remain infection‐free, many suffer multiple severe, life‐threatening, or fatal infectious events. The primary aim of this study was to explore severe and life‐threatening infections post licensed CAR‐T therapy in large B‐cell lymphoma, with a focus on the role of disease burden and disease sites in assessing individual risk. We sought to understand the cohort of patients who experience ≥2 infections and those at the highest risk of infectious NRM. Our analysis identifies a higher disease burden after bridging therapy as associated with infection events. Those developing ≥2 infections emerged as a uniquely high‐risk cohort, particularly if the second (or beyond) infection occurred during an episode of immune effector cell‐associated neurotoxicity syndrome (ICANS) or while on steroids and/or anakinra for ICANS. Herein, we also describe the first reported cases of “CAR‐T cold sepsis,” a phenomenon characterized by the lack of an appreciable systemic inflammatory response at the time of detection of infection. We propose a risk‐based strategy to encourage heightened clinician awareness of cold sepsis, with a view to reducing NRM.