Hemoglobin A1c (HbA1c) testing can be inaccurate in persons with elevated amounts of Hemoglobin F, or with abnormal hemoglobins found in sickle cell trait, HbC trait and HbE trait. These variants are more prevalent in African and Asian Americans, the same demographic that has an increased risk of diabetes. Variant hemoglobins might cause a false increase or decrease in HbAlc, depending on methodology and manufacturer. Case studies of two African American patients, one with and one without variant hemoglobins, are presented. The major methods used to assay HbAlc, immunoassay, HPLC and boronate affinity are described, and compared for their ability to detect variant hemoglobins. An algorithm is proposed to test new patients using the HPLC method to identify or rule out the presence of the most common variant hemoglobins. Patients with variant hemoglobins can subsequently be assigned to HbAlc methods proven to be accurate in the presence of those hemoglobins.