Abstract Objective To test the hypothesis that persons with the R230C allele of ABCA1 show a decreased glycemic response to glyburide. This polymorphism is exclusively found in Ameri-indian populations and is associated with type 2 diabetes. Research design and methods This is a single blind controlled study including participants with type 2 diabetes (fasting glucose levels 126-250mg/dl and HbA1c 7%–10%) managed with metformin and a lifestyle program. Each person with the risk allele (R230C) was matched by age, gender and BMI to three others with the wild type variant (R230R). Following a four week stabilization period, only participants with a greater than 70% adherence to metformin and a stable body weight were prescribed glyburide therapy for a further 16weeks. The main outcome variable was the glyburide dose required to achieve treatment goals. Results No significant difference was observed in the glucose lowering effect of glyburide between subjects with the R230C and R230R alleles. However, the dose of sulfonylurea was significantly higher in the R230C participants compared with the R230R subjects (3.3±2.1 vs 6.3±5mg/day, p<0.001). A higher percentage of R230C participants required at least 5mg of glyburide per day to achieve treatment goals. The glyburide dose was determined by the presence of the risk allele, among other factors. Conclusions Patients with type 2 diabetes who have the R230C allele of ABCA1 needed a higher dose of glyburide in order to achieve the same glucose lowering effect as that in persons with the wild type variant.