NKG2D receptor-ligand interaction triggers NK cell-mediated cytolysis and IFN-gamma secretion. IFN-gamma produced by NK cells has been found to promote the interaction between NK cells and monocytes; however, the underlying mechanism remains elusive. We demonstrate here that IFN-gamma exclusively induced or upregulated the expression of MHC class I chain-related (MIC) molecules, which are ligands of the NKG2D receptor, on the surface of human monocytes of the PBMC population. The IFN-gamma-induced MIC molecules on monocytes played an essential role in triggering the activation of NK cells because mAb-mediated masking of the MIC molecules and the inhibition of cell-to-cell contact using transwell inserts significantly abolished NK cell activation. Meanwhile, membrane-bound IL-15 (mIL-15) was concomitantly induced with MIC molecules on IFN-gamma-treated monocytes and played an essential role in protecting NK cells cocultured with monocytes from MIC-induced NKG2D down-modulation. Therefore, we conclude that the IFN-gamma-induced MIC molecules participated in monocyte/NK cell interaction and that this interaction also involved mIL-15.