Human decidual large granular lymphocytes are capable of killing both normal trophoblast and choriocarcinoma cells after stimulation with recombinant interleukin-2 (rIL-2) in vitro. We now show that pre-treatment of normal trophoblast and JEG-3 choriocarcinoma cells with interferon-gamma (IFN-gamma) protects these target cells from killing by decidual effectors, although pre-treatment with interferon-alpha (IFN-alpha) had no such effect. In contrast, JAR choriocarcinoma cells were readily killed before and after exposure to both IFN-gamma and IFN-alpha. This protective effect might be due to upregulation of non-classical trophoblast HLA Class I molecules, as IFN-gamma but not IFN-alpha enhances Class I surface expression in both normal trophoblast and JEG-3 choriocarcinoma cells. JAR cells, however, are constitutively and inductively negative for Class I expression.