AN important feature of natural killer (NK) cell activity is the lysis of cells that have extinguished expression of some or all class I major histocompatibility (MHC) molecules(1-7). Accordingly, the Ly49A NK-cell antigen receptor has been shown to deliver an inhibitory signal to NK cells on encounter with D-d or D-k class I MHC on target cells(4). Ly49A belongs to a family of eight or more highly related, tightly linked genes(2,8-10). Expression of Ly49A and Ly49C, another member of the Ly49 family with distinct MHC specificity, define subpopulations of NK cells that are only partly overlapping(10-12). The mechanisms regulating the expression of Ly49 family members are unknown. We show here that the Ly49A and Ly49C NK-cell receptors are each subject to allelic exclusion. Because Ly49 genes are not thought to undergo DNA rearrangement(13,14), allelic exclusion of Ly49 genes could involve a mechanism distinct from that used by B and T lymphocytes(15,16) and is likely to play an important role in the genesis of a putative NK-cell repertoire specific for class I molecules.