Abstract Acute myeloid leukemia (AML) is a malignant proliferative disorder in which leukemic cells fail to terminally differentiate and accumulate in the blood and bone marrow. Standard AML therapy requires intensive chemotherapy with a low rate of durable remission and is associated with significant treatment-related toxicity, especially in elderly patients. Therefore, new therapeutic options for the treatment of AML are urgently needed. We previously reported that the novel angiogenic inhibitor, angiocidin, induces differentiation of monocytes to macrophages. Here we investigate the effects of angiocidin on AML cells lines and primary AML cells. Differentiation was assessed by flow cytometry measuring the increase in expression of cell surface marker characteristic of normal macrophages. Four AML cell lines (THP-1, Mono-mac-1, HL-60 and MV4-11) and 5 of 10 primary human AML samples showed evidence of differentiation when cultured in vitro for 24h with 10μg/mL angiocidin. Additionally, we found that angiocidin promoted secretion of a number of cytokines from the cell lines as well as patient cells. We next evaluated the effect of angiocidin on a xenotransplanted primary human AML sample engrafted in NSG mice. We found angiocidin monotherapy reduced the human AML burden in bone marrow by 63% relative to untreated control. Interestingly, angiocidin+cytosine arabinoside (Ara–C) combination therapy reduced human AML in bone marrow by 79%. We believe the combination of in vitro data supporting the capacity of angiocidin to drive differentiation in multiple AML cell lines and primary human AML samples and its activity in a xenotransplantation model that reproduces the human disease is significant. These observations support the continued evaluation and development of angiocidin as a potential novel, non-toxic therapy for AML.