We describe two unrelated patients, both heterozygous for an unstable hemoglobin (Hb) variant named Hb Calgary (HBB: c.194G>T) that causes severe hemolytic anemia and dyserythorpoietic, resulting in transfusion dependence and iron overload. The molecular pathogenesis is a missense variation on the β-globin gene, presumed to lead to an unstable Hb. The phenotype of Hb Calgary is particularly severe presenting as transfusion-dependent anemia in early infancy, precluding phenotypic diagnosis and highlighting the importance of early genetic testing in order to make an accurate diagnosis.