We explored the use of irreversible electroporation (IRE) and high-frequency irreversible electroporation (H-FIRE) to induce cell death of tumor-initiating cells using a mouse ovarian surface epithelial (MOSE) cancer model. Tumor-initiating cells (TICs) can be successfully destroyed using pulsed electric field parameters common to irreversible electroporation protocols. Additionally, high-frequency pulses seem to induce cell death of TICs at significantly lower electric fields suggesting H-FIRE can be used to selectively target TICs and malignant late-stage cells while sparing the non-malignant cells in the surrounding tissue. We evaluate the relationship between threshold for cell death from H-FIRE pulses and the capacitance of cells as well as other properties that may play a role on the differences in the response to conventional IRE versus H-FIRE treatment protocols.