The NovoTTF-100A is an FDA approved device for the treatment of recurrent Glioblastoma. However, the precise nature of its effects on cells that support its clinical efficacy is poorly understood. We have found that the alternating electric fields generated by the NovoTTF-100A (TTFields) disrupt cells during the metaphase to anaphase transition. Cells exposed to TTFields during mitosis appear normal within metaphase, but exhibit prolonged anaphase accompanied by random and uncontrolled membrane contractions referred to as mitotic blebbing arising from dysregulation of contractile elements normally localized to the cytokinetic furrow. This phenomenon leads to aberrant mitotic exit, leading to decreased proliferation and increased apoptosis that is influenced by p53 mutational status. Further analysis demonstrates that treated cells exhibited features of so-called immunogenic cell death capable of stimulating immune responses deranged cells. The ability of alternating electric fields to thus affect cellular physiology is dependent on their ability to perturb the function of specific proteins that possess high dipole moments. The Septin heterotrimer is composed of Septins 2, 6 and 7 and has a high dipole moment of 2711 Debyes. This Septin complex is essential for the organization and the regulation of cytokinetic furrow contraction which results in daughter cell formation. Importantly, perturbation of Septins or their binding partners is reported to result in mitotic catastrophe similar to that observed during TTFields exposure. We report that TTFields perturb normal Septin localization during both mitosis and cell spreading demonstrating a direct effect of TTFields on a protein involved in mitosis. Together, these data strongly support a model that explains how TTFields interfere with normal mitotic progression by disrupting mitotic furrow regulation causing mitotic catastrophe and aberrant mitotic exit. This leads to a form of immunogenic cell death that may sufficiently reduce intratumoral immune privilege to allow for tumor elimination in some patients.