Glycosylated hemoglobin (HbA1C) is a routinely measured parameter to monitor long-term glycemic control in people with diabetes mellitus. The presence of hemoglobin (Hb) variants can affect the accuracy of HbA1C methods. Hb E variant is the most common Hb variant in South-east Asia and North-east India. In the presence of Hb E, HbA1C may not be detectable by ion-exchange chromatography (high-pressure liquid chromatography), but may be estimated by immunoassay technique and boronate affinity chromatography. However, the result may be underestimated when correlated with plasma glucose and serum fructosamine levels. Clinicians should be aware of this limitation of HbA1C estimation in patients with Hb E and other Hb variants.