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We present a case of acute myeloid leukemia (AML) with myelodysplasia-related changes that presented as thrombotic thrombocytopenic purpura (TTP). Our patient presented with the classic pentad of TTP symptoms: anemia, thrombocytopenia, fever, elevated creatinine, and altered mental status. After a failure to respond to plasmapheresis therapy, we proceeded with a bone marrow biopsy and fluorescent in situ hybridization, which supported formal diagnosis of AML with myelodysplasia-related changes. Our case is an extremely rare presentation of a rare condition, as there have been no reported cases of AML with myelodysplasia-related changes presenting as TTP., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Kucharik et al.)