OBJECTIVE SS is a chronic inflammatory condition characterized by systemic and tissue-specific autoimmune features. In view of recent findings indicating a role for killer cell immunoglobulin-like receptors (KIRs) in the pathogenesis of other autoimmune rheumatic disorders such as SSc, and the autoimmune disorders RA and PsA, we sought to determine whether KIRs predict general or specific susceptibility in SS. METHODS Eleven separate KIR genes were typed using PCR sequence-specific primers on genomic DNA from 72 patients diagnosed with primary SS and a control panel consisting of 223 blood donors. RESULTS We found no individual KIR genes to be associated with SS. In contrast, 11 patients with primary SS (15%) and 9 control blood donors (4%) had KIR genotypes with the activating KIR2DS2 in the absence of its corresponding inhibitory homologue KIR2DL2 (P = 0.01). Further analysis of these individuals showed that seven SS patients were positive for HLA-C ligand for KIR2DS2 only compared with one control sample (P = 0.00026). CONCLUSION The genetic combination of KIR2DS2+ and KIR2DL2- in the presence of HLA-C ligand specific for activating KIR2DS2 is associated with primary SS. This implies that autologous KIR-ligand interaction is a contributory factor to predisposition for this disease.