Myristica fragrans seed from Myristica fragrans Houtt (Myristicaceae) has various pharmacological activities peripherally and centrally. The present study aims to investigate the effect of the methanol extract of Myristica fragrans seed (MF) on kainic acid (KA)-induced neurotoxicity in primary cultured rat cerebellar granule neuron. MF, over a concentration range of 0.05 to 5 μg/ml inhibited KA (500 μM)-induced neuronal cell death, which was measured by trypan blue exclusion test and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay. MF (0.5 mug/ml) inhibited glutamate release into medium induced by KA (500 μM), which was measured by HPLC. Pretreatment of MF (0.5 mug/ml) inhibited KA (500 μM)-induced elevation of cytosolic calcium concentration ([Ca2+]c), which was measured by a fluorescent dye, Fura 2-AM, and generation of reactive oxygen species (ROS). These results suggest that MF prevents KA-induced neuronal cell damage in vitro.