Macrocytic anemia is divided into megaloblastic and nonmegaloblastic causes, with the former being more common. Megaloblastic anemia results from impaired DNA synthesis, leading to release of megaloblasts, which are large nucleated red blood cell precursors with chromatin that is not condensed. Vitamin B12 deficiency is the most common cause for megaloblastic anemia, although folate deficiency also can contribute. Nonmegaloblastic anemia entails normal DNA synthesis and typically is caused by chronic liver dysfunction, hypothyroidism, alcohol use disorder, or myelodysplastic disorders. Macrocytosis also can result from release of reticulocytes in the normal physiologic response to acute anemia. Management of macrocytic anemia is specific to the etiology identified through testing and patient evaluation.