Trophoblast cells from normal first trimester pregnancies have been shown to express the nonclassical Class I molecule, HLA-G, which is nonpolymorphic and has a heavy chain of 40 kDa. These HLA-G-expressing trophoblast cells infiltrate into maternal decidua, which contains abundant uterine-specific CD56bright natural killer (NK) cells. We believe HLA-G may act as a protective molecule against decidual NK lysis and thus allow trophoblast survival in the maternal tissues. To test this hypothesis, we have constructed HLA-G and HLA-A2 transfectants using LCL 721.221 HLA-null cells. We observed that both of these antigens protected target cells from NK effectors isolated from decidua or peripheral blood, although the effect of HLA-G is not as marked as that of HLA-A2. Our results, therefore, show that in this experimental system expression of a nonclassical Class 1 HLA molecule is also correlated with NK resistance in the same way as a classical Class I HLA molecule.