A 53-year-old asymptomatic African American man was evaluated for a lifelong history of anemia and thrombocytosis resulting from a splenectomy performed in childhood for unknown reasons. His complete blood count showed red blood cells, 5.79 × 10 6/μL; hemoglobin, 10.5 g/dL; mean corpuscular volume, 55.8 fL; and platelets, 878 × 10 9/L. Iron studies were normal. Hemoglobin electrophoresis showed hemoglobin A (56%), elevated hemoglobin A2 (3.9%), hemoglobin S (39.4%), and hemoglobin F (0.7%). These findings support β-thalassemia with hemoglobin S trait. The peripheral smear red blood cell count showed marked anisopoikilocytosis with elliptocytes (>30%), dacrocytes, sickle cells, and Howell-Jolley bodies (Wright-Giemsa stain; original magnification ×100, oil immersion). A bone marrow biopsy was performed, which revealed normal morphology and cytogenetics, ruling out a myeloproliferative disorder. The patient's father had hemoglobin S trait, but there is no other history of hemoglobinopathy.The smear findings illustrated are highly unusual for hemoglobin S trait and β+ thalassemia, which would have mild microcytic anemia (mean corpuscular volume, 70-80 fL) with increased target cells and rare sickle cells. In this case, anisopoikilocytosis was prominent, including >30% elliptocytes. This is diagnostic of a red cell membrane defect, such as hereditary elliptocytosis. The morphology revealed the probable cause for the remote splenectomy and provides important information for family members.