Summary Killer cell inhibitory receptors and CD94-NKG2-A/B heterodimers are major histocompati- bility complex class I-specific inhibitory receptors expressed by natural killer cells, T cell anti- gen receptor (TCR)- g / d cells, and a subset of TCR- a / b cells. We studied the functional in- teraction between TCR- g / d and CD94, this inhibitory receptor being expressed on the majority of g / d T cells. When engaged by human histocompatibility leukocyte antigen class I molecules, CD94 downmodulates activation of human TCR- g / d by phosphorylated ligands. CD94-mediated inhibition is more effective at low than at high doses of TCR ligand, which may focus T cell responses towards antigen-presenting cells presenting high amounts of anti- gen. CD94 engagement has major effects on TCR signaling cascade. It facilitates recruitment of SHP-1 phosphatase to TCR-CD3 complex and affects phosphorylation of Lck and ZAP-70 kinase, but not of CD3 z chain upon TCR triggering. These events may cause abortion of proximal TCR-mediated signaling and set a higher TCR activation threshold.