Capsaicin, the pungent algesic substance of the red pepper is known to be a neurotoxic substance, interrupting the pain conducting pathway. Until recently the neurotoxic effects of capsaicin in adult animals were thought to be limited to peripheral nervous system. Several reports suggest the possibility of central nervous system changes after capsaicin administration to the adult rats. To determine the effects of capsaicin in central nervous system, morphological and biochemical changes were investigated in mouse primary cultured hippocampal neuron. After capsaicin treatment, hippocampal neurons died in dose-and time-dependent manner. Nuclear fragmentation showed that neuronal cell death induced by capsaicin is apoptosis rather than necrosis. And capsaicin treated neurons were stained by cobalt staining and nitric oxide synthase (NOS) histochemical staining. These results indicated that capsaicin induced influx of cation ions. Because neuronal NOS is activated by Ca(2+), capsaicin induced influx of Ca(2+). Agmatine, which is competitive inhibitor of NOS, reduced cell death induced by capsaicin. It seems likely that the process of hippocampal neuron cell death induced by capsaicin correlates with the activation of NOS by Ca(2+) influx.