In vivo injection of the hamster anti‐murine CD3 monoclonal antibody 145 2C11 into BALB/c mice induces a massive systemic release of several cytokines. Very high circulating levels of tumor necrosis factor are detected both by enzyme‐linked immunosorbent assay and L‐929 bioassay 90 min following a single injection of 10 μg/mouse 145 2C11. Peak circulating levels of exclusively T cell‐derived products such as interferon‐γ, interleukin 2 and interleukin 3 are also detected 90 min to 8 h post‐injection. Importantly, this cytokine release is transient since none of these cytokines are still present 12 to 24 h post‐injection. In parallel to cytokine release, 145 2C11‐treated mice (10 μg/mouse) exhibit somnolence, hypomotility (quantified by actimetry), hypothermia, diarrhea and piloerection. At this dosage, the physical reaction is not lethal and reverses in all mice by 48 h post‐injection. Severe but again reversible anatomopathological changes are also observed: massive cellular depletion, necrosis and edema of lymphoid organs, leakage syndrome and inflammatory cell infiltrates of the lung, cell vacuolization, necrosis and vascular congestion of the liver. All these data are similar to the clinical and immunological manifestations of the OKT3‐induced reaction in patients and, thus, provide an invaluable experimental tool to study its mechanisms and explore its prevention.