Hippocampal tissue slices were made hypoxic for 4-10 min and then reoxygenated for 60-120 min. Postsynaptic evoked potentials were recorded and extracellular DC potential was monitored continuously in stratum (st.) pyramidale of CA1 and st. granulosum of fascia dentata (FD). In some preparations extracellular potassium ([K+]o) and calcium ([Ca2+]o) were also recorded in both regions. Postsynaptic responses disappeared sooner during hypoxia and were less likely to recover upon reoxygenation in CA1 than in FD. The CA1 region exhibited a spreading depression (SD)-like response to hypoxia more often than did FD. When both regions showed SD-like depolarization, voltage shift and elevation of [K+]o were of greater magnitude and shorter latency in CA1. The probability of posthypoxic recovery of synaptic transmission was inversely related to the time spent in the SD-like state in both CA1 and FD. We conclude that the selective vulnerability of CA1 neurons to hypoxic and ischemic damage may be due, at least in part, to the region's propensity to undergo prolonged and severe SD-like depolarization.