Palytoxin (PTX) is a potent marine toxin that causies serious damage to various tissues and organs. It has been reported to affect the transport of cations across the plasma membranes, which is commonly recognized as being the principal mechanism of its highly toxic action on mammals, including humans. However, although some marine toxins have been shown to cause toxic effects on the nervous system by interfering with the transmission of nerve impulses, the effect of PTX on neuronal cells has not yet been fully elucidated. Therefore, the toxic action of PTX on PC12 cells was examined as an in vitro model experiment to elucidate the neurotoxic properties of this toxin, and PTX was shown to reduce the viability of PC12 cells in a concentration-dependent manner. The cytotoxic action of PTX was not significantly altered by the presence of the antioxidant N-acetylcysteine and reduced-form glutathione in the cultures. Fluorescence staining of the cells and the electrophoretic analysis of genomic DNA showed that PTX failed to cause chromatin condensation and DNA fragmentation within the cells. On the other hand, the exposure to PTX caused positive staining of the cytoplasmic space of the cells with propidium iodide and the release of lactate dehydrogenase into the culture medium. Based on these observations, PTX is considered to cause cell death as a consequence of disrupting the plasma membranes, thus causing nonoxidative necrotic damage to PC12 cells. Copyright © 2011 John Wiley & Sons, Ltd.