OBJECTIVE To explore the effect of KIR/HLA ligand matching which mediates activated or inhibitory signal pathways on acute rejection (AR) after kidney transplantation. METHODS HLA and KIR genotype assortments were analyzed in 53 donor/recipient pairs of kidney transplantation. The recipients were divided into AR group (GI, n=19) and stable renal function group (GII, n=34) based on the early graft function. The impact of donor HLA, recipient KIR and distinct KIR/HLA class I ligand combinations on acute rejection after kidney transplantation was studied. RESULTS No significant differences were found in donor HLA-C1/2, HLA-A3, HLA-A11, or HLA-Bw4 between GI and GII groups. The frequency for KIR2DL2/2DS2 and KIR genotype assortment (AA) of the recipients in GI group were significantly lower than that in GII group (26.3% vs 55.9%, P=0.038; 31.6% vs 67.6%, P=0.011). The incidence of AR was significantly lower in donor HLA-C1/1 than in non-C1/1 (31.6% vs 46.7%, P>0.05), and lower in recipient KIR genotype assortment (AA) than in non-AA (20.7% vs 52.2%, P=0.011). A significant higher number of matches for the KIR2DL2/ HLA-C1 and KIR2DL3/HLA-C1 were observed in GII group (P=0.030, P=0.028). CONCLUSIONS Distinct KIR/HLA class I ligand combinations between the donor and recipient (such as KIR2DL2/ HLA-C1 and KIR2DL3/HLA-C1) may reduce the incidence of AR. A good KIR/HLA class I ligand matching will benefit the survival of the renal allograft.