OKT3, an anti-CD3 MAB, depletes T cells in vivo and is among the most potent inhibitors of acute allograft rejection. The mechanism of this inhibition is unknown. The present studies investigate whether anti-CD3 antibodies have the ability to crosslink CD3 on two different cells and induce TCR-dependent antibody-bridged cell-mediated cytolysis (TCR-ABCMC) between T cells. Two different anti-CD3 antibodies (OKT3 and CD3,3) and OKT3 F(ab')2 were all highly effective in inducing cytolysis of CD8+ and CD4+ T cells by CD8+ T cells, and CD8+ T cells by CD4+ T cells. Monovalent OKT3 Fab was 25-125-fold less potent than OKT3 F(ab')2. Monovalent CD3,X was totally ineffective. The necessity for intercellular bridging was evidenced by the observation that an anti-CD3:anti-CD4 (CD3,4) bispecific MAB (BSMAB) was effective in mediating lysis of CD4+ but not CD8+ T cells by CD8+ T cells. These studies indicate that neither FcR-mediated ADCC nor complement fixation is necessary for bivalent anti-CD3 MAB to lyse T cells. Inter-T cell TCR-ABCMC may be particularly effective in inflammatory tissues, such as rejecting allografts and autoimmune diseases, in which numerous cytolytic T lymphocytes are present in close association with other T cells.