We investigated killer immunoglobulin-like receptors (KIRs) and the human leukocyte antigen (HLA)-C ligands for the corresponding inhibitory KIRs in Caucasian patients, 304 with systemic lupus erythematosus (SLE) and 90 with scleroderma [or progressive systemic sclerosis (PSS)] compared with 416 Caucasian controls. Compared with controls, KIR2DS1 in the absence of KIR2DS2 was increased in both SLE (P= 0.04) and PSS (P= 0.02). Only 42% of KIR2DS1-positive PSS patients had the appropriate HLA-C ligand for the corresponding inhibitory KIR compared with 61% of KIR2DS1 positive controls (P= 0.02). In the PSS group the presence of at least either activating KIR2DS1 and/or 2DS2 was significantly increased in patients when compared with controls (P= 0.001). This suggests that KIR receptors play a role in susceptibility to both PSS and SLE.