As an MHC class I protein, the disease association of HLA-B27 with inflammatory arthritis has been widely assumed to imply a role for the T cell antigen receptor (TCR) in disease. However, in addition to their classical antigen-presenting role, HLA class I proteins are recognised by members of the killer immunoglobulin receptor (KIR) and leukocyte immunoglobulin-like receptor (LILR/ILT/LIR) families. Unusual properties of HLA-B27 include an ability of free heavy chains (FHC) to reach the cell surface in the absence of beta2m and to maintain their peptide-binding groove in vitro. This review describes immunomodulatory receptors that recognise HLA class I, and the recognition of HLA-B27 in both the classical beta2m-associated and beta2m-independent forms by members of the KIR and LILR families. Alternative recognition of different forms of HLA-B27 by leukocyte receptors could influence the function of cells from both innate and adaptive immune systems, and may indicate a role for various leukocyte populations in HLA-B27-associated inflammatory disease.