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Cancer continues to be a major risk to the health and well being among populations around the world. A new method using ion-ionizing radiation with nanosecond pulsed electric fields (nsPEFs) provides a novel means to treat cancer at local sites. NsPEFs promote cell death in several cell types and here we investigated mechanisms for cell death induction. In murine B16f10 melanoma, murine E4 squamous carcinoma, murine Hep1-6 and human HepG2 hepatocellular carcinoma, nsPEFs induced cell death in 90-95% of cells. Cell death coincides with decreases in the mitochondria membrane potential, increases in YO-PRO-1 uptake and active caspases in the presence or absence of cytochrome c release. The results indicate that nsPEFs induced cell death by multiple apoptosis mechanisms that involve mitochondrial responses, but not necessarily through cytochrome c release. Further, these in vitro studies suggest a potential to induce cell death that bypasses cancer mechanisms that evade apoptosis.