Because of the widespread use of multiparameter hematology instruments, physicians are often presented with patients who have macrocytosis with no obvious cause. Depending on the demographics of an individual practice, folate and vitamin B12 deficiencies may be relatively rare causes of macrocytosis, compared with alcoholism, liver disease, drugs, or myelodysplasia. Initial evaluation should include a carefully taken history and physical examination along with a complete hematologic profile, reticulocyte count, and peripheral blood smear. This initial evaluation should allow systematic consideration of the possible causes. Serum B12 and red cell folate determinations and other studies may then be undertaken as appropriate.