This study was to evaluate the association between ADIPOQ gene variants and type 2 diabetes mellitus (T2DM). TaqMan(®) assay was performed to test the genotypes in T2DM patients (n = 1,105) and normal control subjects (n = 1,107). Serum adiponectin concentration was measured by ELISA kit. The variant genotypes rs7649121AT and rs7649121AT/TT, compared with the AA genotype, were associated with a significantly decreased risk of T2DM [Adjusted OR (95% CI) = 0.79(0.66-0.95), 0.80(0.67-0.96), respectively]. In stratified analysis, rs2241767AG genotype increased the risk of T2DM in obesity group [Adjusted OR (95% CI) = 1.32(1.03-1.69)]. Patients with genotype AG/GG of rs2241767 had lower levels of serum adiponectin than those with the genotype AA (P = 0.044). Haplotype analyses were not significant. Crossover analysis of rs7649121 and environmental risk factor (obesity) indicated that the protect effect of rs7649121AT/TT maybe offset by the environmental risk. Those who exposed to environmental risk factor (obesity) had a chance to attack T2DM compared with those who did not expose to the two factors [Adjusted OR (95% CI) = 1.64(1.30-2.06)]. This study suggested that the ADIPOQ gene polymorphisms were associated with the risk of T2DM in a Chinese Han population.