Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL) 1. Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells) 2, 3, 4, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6) 2, 5. CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden 2, 3, 4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity 2, 3, 4, 5, 6, 7, 8, 9. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2–3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell–derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions.