In addition to being potent immunosuppressants, anti‐CD3 monoclonal antibodies (mAb) are powerful mitogens in both humans and mice. The first antibody injection consistently induced an initial monocyte‐dependent T cell activation with subsequent release of both monocyte‐ and T cell‐derived cytokines (mainly tumor necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ), interleukin (IL) 2, IL 3 and IL 6) into the circulation. This cytokine release is associated with a self‐limiting, often severe, acute physical reaction in both patients and mice. We report here that a single injection of anti‐TNF mAb prior to anti‐CD3 administration not only neutralizes the biological activity of TNF but also strongly affects the release of other cytokines, with notably an up‐regulation of IFN‐γ release and a down‐regulation of IL 3 and IL 6 release. Conversely, pretreatment with anti‐IFN‐γ mAb increases IL 3 and IL 6 production but does not affect TNF levels. Taken together, these data point to a pivotal role of IFN‐γ in the anti‐CD3‐induced cytokine cascade and reveal new regulatory pathways between TNF and IFN‐γ. With regard to the clinical implications of these findings, as anti‐TNF mAb prevents anti‐CD3‐induced sickness in mice, whereas anti‐IFN‐γ does not, such a therapeutic approach might be of value in OKT3‐treated patients.