Metazoan organisms may discriminate between self and non-self not only by the presence of foreign antigens but also by the absence of normal self markers¹. Mammalian adaptive immune responses use the first strategy, with the additional requirement that foreign antigens are recognized in the context of self-major histocompatibility complex (MHC) products at the cell surface². Aberrant cells which fail to express MHC products adequately can therefore avoid detection^2–4. A more primitive but complementary defence system, eliminating such cells on the basis of absent self-markers, is suggested by a re-interpretation^5,6 of phenomena associated with metastasis and natural resistance. We now show that murine lymphoma cells selected for loss of H–2 expression are less malignant after low-dose inoculation in syngeneic hosts than are wild-type cells, and that the rejection of such cells is non-adaptive. On the basis of our data, we suggest that natural killer cells are effector cells in a defence system geared to detect the deleted or reduced expression of self-MHC.