Acute Chest Syndrome (ACS) is a rare but often fatal complication in patients with micro-drepanocytic anemia as in those with beta Sickle Cell Disease (SCD). This case report refers to a female patient with known micro-drepanocytic anemia who was admitted to our ICU due to ACS. Treatment included RBC transfusions with WBC reduction, administration of FFP and plasmapheresis within 48 hours from the ICU admission. At the 3rd ICU day, HbA2 level was found elevated up to 77%. The following ICU days, the patient presented absence of the white series of the blood’s cellular components. After twelve days in the ICU the patient died due to hemodynamic shock and herniation of the brain stem. Given that sickle cell crises are potential precursors of this deadly syndrome, everyday practice should prioritize the prevention of sickle cell crises developing into ACS.