T-lymphocyte activity in the immune system is regulated by the quantity of surface membrane T-cell antigen receptors (TCR). The amount of surface-bound TCR is dependent on the rate of [1] biosynthesis, assembly and intracellular transport of the individual chains composing the TCR/CD3 complex and [2] the internalization and recycling of the receptors. The TCR-ligand interaction augments receptor internalization. In the present paper, we have studied short- and long-term down-regulation of TCR/CD3 complexes with monoclonal anti-TCR/CD3 antibodies, and attempted to determine which component(s) of the TCR/CD3 complex are responsible for these two phenomena. Our data indicate that short- and long-term down-regulation is mediated by different mechanisms, and that the extracellular and/or transmembrane regions of CD3gamma molecules appear to play an important role in chronic TCR/CD3 down-regulation and subsequent deficient re-expression. These results may have important implications for the understanding of induction of T-cell tolerance or anergy.