AbstractThe nonclassical human leukocyte antigen (HLA)‐E and ‐G molecules have previously been shown to inhibit natural killer‐ and cytotoxic T‐lymphocyte‐mediated cell lysis and have also been shown to prevent the proliferation of CD4 T cells and secrete cytokines that appear to be important in the modulation of the Behcet’s disease (BD) immune systems. Polymorphisms in the HLA‐E and HLA‐G genes have been associated with differential expression and function. Thus, we conducted an analysis of the HLA‐E and HLA‐G alleles using Amplification Refractory Mutation System‐polymerase chain reaction (PCR) and PCR‐restriction fragment length polymorphism techniques in a study comprising 312 patients with BD and 486 controls. The HLA‐E*0101 and HLA‐G*010101 alleles were associated with a reduced risk of BD (P = 0.0002, odds ratio (OR) = 0.7 and P = 0.002, OR = 0.7, respectively). By way of contrast, the variants HLA‐E*010302, HLA‐G*010102, G*0105N alleles and 3741_3754ins14bp were all associated with an increased risk of BD (P < 0.0001, OR = 1.6; P = 0.002, OR = 1.8; P = 0.024, OR = 2.0 and P = 0.003, OR = 1.4, respectively). Individuals carrying both the HLA‐E*0101 and the HLA‐G*010101 alleles evidenced significantly lower frequency in the patients than in the controls (35.6% vs 49.6%; P < 0.0001, OR = 0.6). These results indicate that variant HLA‐E and HLA‐G molecules appear to function independently and synergistically, increasing the risk of BD, and may result in an imbalance of lymphocytic functions, which may culminate in the development of BD.