Orthopoxvirus MHC class-I like Protein (OMCP) is encoded by both Cowpox and Monkeypox viruses. This protein has a structure similar to known host-encoded MHC class-I like ligands of NKG2D. OMCP is secreted by infected cells and binds to the NKG2D homodimer as a monomer. OMCP competitively blocks host ligand engagement resulting in a blockade of NK cell activation. Interestingly, OMCP binds to human NKG2D with 14-fold higher affinity than to mouse NKG2D.