Cellular activity of natural killer cells (NK cells) is defined by the balance between activating and inhibitory signals coming from their receptors. With respect to this response, killer immunoglobulin-like receptors (KIR) are unique because of their diversity and capacity to recognize specific human leukocyte antigen (HLA) class I allotypes. Up to the present few studies have experimentally been developed concerning the role of KIR genes in spondyloarthropathies (SpA) and its clear relationship with HLA-B27. However, the role of the HLA-B27 heavy chain homodimers and their possible recognition by KIR receptors in the pathogenesis of spondylarthritides has been studied. Moreover, it has been suggested that NK cells and their receptors could play a role in ankylosing spondylitis (AS) development. Several association studies based on a model in which KIRs synergize with HLAs have also been published. This interaction may generate compound genotypes which provide different levels of activation or inhibition. Furthermore, some of these have been associated with certain SpA, such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA).