Objective To investigate the effect of ATP-binding cassette transport a1 (ABCA1 ) gene R219K polymorphism on the antidiabetic efficacy of Glimepiride, and to explore genetic mechanism of the therapeutic variation of Glimepiride. Methods Seventy-six patients with newly-diagnosed T2DM were enrolled in our study and treated with Glimepiride for 12 weeks. Clinical biochemical makers were detected before and after treatment. Genotyping of ABCA1 gene R219K was performed in all patients. Results Three genotypes RR, RK and KK were detected in ABCA1 gene R219K polymorphism. There were no statistically significant differences in fasting blood glucose (FBG), 2 h postprandial blood glucose (2h-BG) or glycosylated hemoglobin (HbA1c) among the patients with different genotypes before treatment (P > 0.05). FBG, 2h-BG and HbA1c in all patients decreased significantly after 12 weeks of treatment with Glimepiride (P < 0.05). After treatment with Glimepiride for 12 weeks, the Δ2h-BG level in the patients with RK genotype or KK genotype was remarkly higher than that in the patients with RR genotype (P < 0.05), while the 2h-BG and HbA1c levels in the patients with RK genotype or KK genotype were remarkly lower than those in the patients with RR genotype (P < 0.05). Conclusions ABCA1 gene R219K polymorphysm is detected in Chinese Han population with T2DM. Our study showed that ABCA1 gene R219K polymorphism might be relevant to the antidiabetic efficacy of Glimepiride. T2DM patients with RK or KK genetype may be more sensitive to Glimepiride than those with RR genotype.