The three most common causes of macrocytosis--vitamin B12 or folate deficiency, liver disease, and reticulocytosis--usually can be differentiated on the basis of red cell indexes and morphologic findings. Bone marrow studies are not indicated. In reticulocytosis, the mean corpuscular volume (MCV) rarely exceeds ll0 cu mu and a reticulocyte count quickly establishes the diagnosis. In liver disease, macrocytosis is also mild and uniform. The RBCs are round. In megaloblastic anemia, the MCV may exceed 150 cu mu. The RBCs vary considerably in size and shape. The macrocytes tend to be oval. Serum vitamin B12 determination remains the best test for unmasking vitamin B12 deficiency. It should be ordered in conjunction with serum and red cell folate determinations in the course of investigating a macrocytic anemia. When vitamin B12 deficiency has been established, a Schilling test or plasma uptake test is indicated to pinpoint the cause.