Objective To explore the involvement of calcium in the mechanism of hypoxic/hypoglycemic insults and nerve growth factor (NGF) protection.Methods Neuron viability and lactate dehydrogenase (LDH) efflux in the bathing medium in cerebral cortex cultures from fetal rats were measured. Calcium fluorescent indicator Fura-2/AM was used to measure the intracellular free calcium ([Ca2+]i).Results Massive neuronal death occurred 16-24 h following the onset of hypoxia/hypoglycemia. NGF (3-100 μg·L-1) dose-dependently attenuated 24 h hypoxia/hypoglycemia-induced efflux of LDH and elevated the number of surviving neurons. Hypoxia/hypoglycemia induced a reduction in [Ca2+]i in early stage and a large elevation of [Ca2+]i in later period. NGF 50 μg·L-1 increased [Ca2+]i to normal limits during the early stages of hypoxia/hypoglycemia and prevented the later elevation in [Ca2+]i.Conclusion The [Ca2+]i elevation may be responsible for the cell damage in oxygen/glucose deprived cultures. NGF protects cerebral cortical neurons against hypoxic/hypoglycemic insults via stabilizing [Ca2+]i level or preventing the late rise in [Ca2+]i.