Murine monoclonal antibodies specifically directed at the CD3 molecular complex are widely used in clinical transplantation. They are potent inhibitors of immune function and may be administered in association with conventional immunosuppressive drugs. However, their use has been complicated by the severe clinical syndrome that invariably follows the first injections of the antibody. We have shown that this reaction relates to transient T cell activation, with production of a cohort cytokines. This in vivo activating effect is unique to anti-CD3 MoAbs. Furthermore, this property is highly monocyte-dependent, engaging Fc receptors, and thus varies according to the isotype of the administered MoAb. Another anti-T cell MoAb such as the BMA031 directed towards monomorphic determinants of the T cell receptor (TCR) does not promote such massive in vivo activation.