Bone marrow necrosis (BMN) ranges from a localized to a widespread generalized process. Most often seen in patients with leukemia and other malignant conditions, generalized BMN has also been observed in patients with sickle cell disease (SCD), where it is almost certainly a consequence of blood vessel occlusion. Activation of the clotting system seems to play a role in this clinical setting. Systemic fat embolism and acute multi-organ failure syndrome can also complicate BMN in patients with SCD. We describe here 3 cases of BMN associated with SCD. Each patient exhibited an unusually severe vaso-occlusive crisis accompanied by persistent fever, a high level of serum lactate dehydrogenase, leukoerythroblastosis, and large numbers of nucleated red cells. Despite such suggestive clinical features, diagnosis of BMN still requires a bone marrow biopsy. Particularly in patients with SCD, the early institution of transfusion therapy can be life-saving. The ominous prognosis ascribed to generalized BMN seems to reflect the poor outcome of such underlying conditions as leukemia; however, the prognosis of generalized BMN is not so poor in association with SCD and other nonmalignant states.