The 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.