Introduction: Mutations in the ABCG8 gene are classically associated with sitosterolemia, a rare autosomal recessive disorder characterized by excessive intestinal absorption and decreased biliary excretion of plant sterols. With only 100 cases of sitosterolemia worldwide, hemolytic anemia has an estimated occurrence of 6.8%. Stomatocytosis, macrothrombocytopenia, and increased osmotic fragility of RBC were described, hypothetically caused by the abnormal incorporation of plant sterols into RBC and platelet membranes due to elevated plasma levels, altering membrane composition Case Presentation: A 32-year-old Yemeni woman with IBS in remission, presented with worsening fatigue, dizziness, headaches, and regular menstrual cycles with moderate flow. On initial evaluation: Microcytic anemia with beta-thalassemia trait. Iron deficiency was excluded. Peripheral blood smear showed teardrop cells, schistocytes, elliptocytes, basophilic stippling and giant platelets with high mean platelet volume. Undetectable haptoglobin, high LDH and reticulocyte count, but negative Direct Coombs and moderately increased osmotic fragility. Abdominal ultrasonography showed moderate splenomegaly. Anemia persisted despite folic acid, iron and corticosteroids oral treatment. A comprehensive hereditary HA panel identified a heterozygous mutation in the ABCG8 gene. Transient improvement was achieved with intravenous iron infusions and 2 cycles of intravenous immunoglobulin. Her hemoglobin declined accompanied by worsening exertional dyspnea and palpitations when she was pregnant. Following uneventful delivery, the patient's hemoglobin stabilized at 9 g/dL. Postpartum PBS showed a few tear drops and schistocytes, hypo and polychromasia, micro and anisocytosis. She remains on oral folate and iron and is monitored outpatient. Discussion: To our knowledge, this is the first documented case of a heterozygous ABCG8 mutation presenting without any of the characteristic clinical features of sitosterolemia. The presence of a heterozygous ABCG8 mutation raises suspicion for a genetic contribution to this patient’s hemolytic anemia, especially in the absence of other identifiable causes. A definitive link cannot be established without further studies, but this mutation remains the most likely contributor. Conclusion: This case highlights the need to consider rare genetic mutations in unexplained anemia and the importance of ongoing research in such presentations, particularly in treatment-resistant cases where anemia does not respond to ongoing steroid therapy.