Natural killer cells are an important component of innate resistance to viruses, bacteria, certain parasites, and tumors. The activating receptor natural killer group 2D (NKG2D) plays a critical role in the elimination of tumor cells by cytotoxic effector cells. It has been shown that the strength of an antitumor immune response might be critically dependent on NKG2D ligard surface levels. Thus, it is essential to regulate the expression of NKG2D ligands in order to ensure effective tumor immunosurveillance and the elimination of pathogen-infected cells. In the present study, we found that interferon (IFN)-alpha and IFNgamma exert opposing effects on major histocompatibility complex class I-related chain A (MICA) expression in human tumor cells. IFNalpha promotes expression of the NKG2D ligand MICA in tumor cells and therefore enhances their sensitivity to natural killer lysis. In contrast, IFNgamma exerts the opposite effect. IFNalpha promotes MICA expression at the level of transcription by augmenting MICA promoter activity. IFNgamma modulates MICA expression not only at the transcriptional level, but also at the post-translational level by promoting proteolytic cleavage by matrix metalloproteinases. Further study is needed to clarify the precise regulatory mechanisms. The pathways involved in NKG2D ligand induction might represent a promising target for improving immune responses to cancer or infections.