Resistance to parental bone marrow (BM) grafts in F1 hybrid recipients is due to natural killer (NK) cellmediated rejection triggered through “missing self” recognition. “Hybrid resistance” has usually been investigated in lethally irradiated F1 recipients in conjunction with pharmacological activation of NK cells. Here, we investigated BMdirected NKcell alloreactivity in settings of reduced conditioning. Nonlethally irradiated (13 Gy) or nonirradiated F1 (C57BL6 BALB/c) recipient mice received titrated doses (520 x 106) of unseparated parental BALB/c BM without pharmacological NK cell activation. BM successfully engrafted in all mice and multilineage donor chimerism persisted longterm (24 weeks), even in the absence of irradiation. Chimerism was associated with the rearrangement of the NKcell receptor repertoire suggestive of reduced reactivity to BALB/c. Chimerism levels were lower after transplantation with parental BALB/c than with syngeneic F1 BM, indicating partial NKmediated rejection of parental BM. Activation of NK cells with polyinosinicpolycytidylic acid sodium salt poly(I:C), reduced parental chimerism in nonirradiated BM recipients but did not prevent hematopoietic stem cell engraftment. In contrast, equal numbers of parental lymph node cells were completely rejected. Hence, hybrid resistance leads to incomplete rejection of parental BM under reduced conditioning settings.