The Qa-1b/Qdm tetramer binds to CD94/NKG2 receptors expressed at high levels on ∼50% of murine NK cells. Although very few CD8 T cells from naive mice express CD94/NKG2 receptors, ∼50% of CD8 T cells taken from mice undergoing a secondary response against Listeria monocytogenes (LM) are CD94high and bind the tetramer. Although CD94int NK cells do not bind the tetramer, CD94int CD8 T cells do, and this binding is dependent on the CD8 coreceptor. We found that the extent of apoptosis in CD8 T and NK cells was inversely related to the expression of CD94, with lower levels of apoptosis seen in CD94high cells after 1-3 days of culture. The difference in CD8 T cell survival was evident as early as 6 h after culture and persisted until nearly all the CD94neg/int cells were apoptotic by 48 h. In contrast, expression of inhibitory Ly-49A,G2,C/I molecules was associated with higher levels of apoptosis. Cross-linking CD94/NKG2 receptors on CD8 T cells from a mouse undergoing an LM infection further reduced the percentage of apoptotic cells on the CD94-expressing populations, while cross-linking Ly-49I had no effect on CD8 T cells expressing Ly-49I. Cross-linking CD3 on CD8 T cells from a mouse undergoing a secondary LM infection increases the extent of apoptosis, but this is prevented by cross-linking CD94/NKG2 receptors at the same time. Similar results were observed with NK cells in that the CD94high population displayed less apoptosis than CD94int cells after 1-3 days in culture. Therefore, the expression of CD94/NKG2 is correlated with a lower level of apoptosis and may play an important role in the maintenance of CD8 T and NK cells.