Human cytomegalovirus (HCMV) is a ubiquitous pathogen that establishes lifelong infection and causes potentially fatal diseases in the presence of immune dysfunction. Natural killer (NK) cells in particular are critical for immune control of HCMV. The activity of NK cells is governed innately by germline-encoded receptors focused on the recognition of major histocompatibility complexes (MHCs), which are downregulated by several viruses, including HCMV. Many viral immunoevasins are known to target NK cell activity, minimizing compensatory activation in response to a paucity of MHCs, but none have yet been shown to interact with killer cell immunoglobulin-like receptors (KIRs). Using reporter cell lines expressing individual KIRs to screen target cells infected with deletion mutants of HCMV or adenoviral vectors expressing individual proteins derived from HCMV, we identified a hypervariable viral immunoevasin that engaged inhibitory and stimulatory lineage II KIRs. Direct binding was confirmed using KIR-Fc molecules, recombinant immunoevasin tetramers, and surface plasmon resonance. The functional consequences of engagement were determined using flow cytometry to assess cytotoxicity, cytokine production, and proliferation among NK cell populations, which were differentially impacted in a KIR-specific manner and further influenced by sequence variation in the immunoevasin gene across different strains of HCMV. These results identify a novel mechanism by which HCMV evades the activity of NK cells and potentially shed light on the evolutionary selection of KIRs.