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Microsecond pulsed electric fields (PEF) have previously been used for various tumour therapies, such as gene therapy, electrochemotherapy and irreversible electroporation (IRE), due to its demonstrated ability. However, recently nanosecond pulsed electric fields (nsPEF) have also been used as a potential tumor therapy via inducing cell apoptosis or immunogenic cell death to prevent recurrence and metastasis by interacting with intracellular organelles. A large proportion of the existing in-vitro studies of nsPEF on cells also suggests cell necrosis and swelling/blebbing can be induced, but the replicability and potential for other effects on cells suggesting a complicated process which requires further investigation. Therefore, this study investigated the effects of pulse width and intensity of nsPEF on the murine melanoma cells (B16) and normal murine fibroblast cells (L929) through electromagnetic simulation and in-vitro experiments. Through examining the evolution patterns of potential difference and electric fields on the intracellular compartments, the simulation has shown a differential effect of nsPEF on normal and cancerous skin cells, which explains well the results observed in the reported experiments. In addition, the modelling has provided a clear evidence that a few hundreds of ns PEF may have caused a mixed mode of effects, i.e. a 'cocktail effect', including cell electroporation and IRE due to an over their threshold voltage induced on the plasma membrane, as well as cell apoptosis and other biological effects caused by its interaction with the intracellular compartments. The in-vitro experiments in the pulse range of the hundreds of nanoseconds showed a possible differential cytotoxicity threshold of electric field intensity between B16 cells and L929 cells. [ABSTRACT FROM AUTHOR]