Calbindin-D28K has been implicated in the regulation of neuronal cell death. Previously, we demonstrated that calbindin-D28Kprevents staurosporine (STS)-induced caspase activation and subsequent apoptosis in a neuronal cell line. However, the role ofcalbindin-D28K in STS-induced activation of calpain and necrotic cell death was not identified. Staurosporine induced the elevationof intracellular calcium after 1 hr of treatment. Overexpression of calbindin-D28K and presence of a calcium chelator, BAPTA,prevented the increase of calcium in STS-treated cells. Cleavage of Bax by calpain was prevented by the overexpressed calbindin-D28K. Permeabilization of the plasma membrane, a factor in necrosis, as well as apoptotic change of the nucleolus induced by STS,was prevented by calbindin-D28K. Thus, our study suggests that calbindin-D28K may exert its protective functions by preventingcalpain activation in necrotic cell death, in addition to its effect on the caspase-apoptosis pathway.