Natural killer cells have been reported to be able to kill various transformed and virus-infected target cells. It was recently observed that NK cells also could kill syngeneic dorsal root ganglia (DRG) neurons by a perforin-dependent mechanism. We demonstrate here that this phenomenon does not reflect a general ability of NK cells to kill neurons in culture. While DRG neurons of the peripheral nervous system were readily killed, ventral spinal cord neurons and hippocampal neurons of the central nervous system (CNS) were resistant to lysis. The resistance to NK cell-mediated lysis of the latter neurons was not related to protection by MHC class I molecules, since similar beta(2)-microglobulin(-/-) neurons were equally resistant to lysis. While exploring other possible molecular mechanisms for the selective triggering of lysis of DRG neurons, we observed that the retinoic acid early inducible gene-1 (RAE-1), the product of which is a ligand for the NK cell-activating receptor NKG2D, was expressed at high levels in the DRG neurons. In contrast, RAE-1 was expressed only at very low levels in the resistant CNS-derived neurons. Blocking NK cells withanti-NKG2D antibodies inhibited NK cell-mediated killing of the DRG neurons. Thus, we demonstrate that NK cell-mediated lysis of DRG neurons correlates with the expression of RAE-1 and that this lysis is dependent on activation of NK cells via NKG2D. This observation demonstrates that NK cells can kill non-pathogen-infected or non-transformed syngeneic cells through activation of the NKG2D receptor.