Anoxia is believed to cause nerve injury and death in part, by inducing sustained, elevated levels of intracellular Ca 2+. The increased concentration of intracellular Ca 2+ is capable, by itself, of inducing nerve injury and death, even without the added stress of anoxia. However, we have recently shown that an increased level of intracellular Ca 2+ is not necessary for anoxia-induce CA1 nerve injury. Since we have observed that extracellular Na + decreases during anoxia, we studied the role of extracellular Na + in anoxia-induced nerve injury. Removal of extracellular Na + and its replacement with the impermeant cation N-methyl- d-glucamine (NMDG +) completely protected freshly dissociated CA1 neurons during and after severe anoxia, for up to 90 min. Intracellular Ca 2+ decreased during anoxia, recovering during reoxygenation. Propidium iodide was excluded from the neurons for as long as Na + was absent. Addition of Na + (by replacing NMDG +) following anoxia resulted in rapid bleb formation, swelling and intracellular Ca 2+ rise. Removal of Na + before the rupture of blebs caused either shrinkage or pinching off of blebs so that the neuron apparently returned to its previous undisturbed state. We conclude that: (1) replacement of Na o + with NMDG + totally prevents anoxia-induced nerve injury as manifested by morphological changes, e.g., swelling, bleb formation and membrane injury; (2) upon re-exposure to Na o + following anoxia in the absence of Na o +, neurons swell and bleb; (3) the appearance of blebs following anoxic exposure in the absence of Na o + is reversible and Na o + dependent. (4) Bleb formation itself is not necessarily immediately lethal to the neuron.