Acute myeloid leukemia (AML) is characterized by the proliferation of immature myeloid lineage blasts. Due to its heterogeneity and to the high rate of acquired drug resistance and relapse, new treatment strategies are needed. Here, we demonstrate that IFN promotes AML blasts to act as effector cells within the context of antibody therapy. Treatment with IFN drove AML blasts toward a more differentiated state, wherein they showed increased expression of the M1-related markers HLA-DR and CD86, as well as of FcRI, which mediates effector responses to therapeutic antibodies. Importantly, IFN was able to up-regulate CD38, the target of the therapeutic antibody daratumumab. Because the antigen (CD38) and effector receptor (FcRI) were both simultaneously up-regulated on the AML blasts, we tested whether IFN treatment of the AML cell lines THP-1 and MV4-11 could stimulate them to target one another after the addition of daratumumab. Results showed that IFN significantly increased daratumumab-mediated cytotoxicity, as measured both by Cr-51 release and lactate dehydrogenase release assays. We also found that the combination of IFN and activation of FcR led to the release of granzyme B by AML cells. Finally, using a murine NSG model of subcutaneous AML, we found that treatment with IFN plus daratumumab significantly attenuated tumor growth. Taken together, these studies show a novel mechanism of daratumumab-mediated killing and a possible new therapeutic strategy for AML.