Intracellular electrophysiologic recordings were performed in brain slices from adult rats to compare the response of brain stem hypoglossal neurons (XII) and layer II/III neocortical neurons (NCX) to two levels of oxygen deprivation (hypoxia, pO2 = 15-20 Torr; anoxia, pO2 = 0 Torr). These recordings were also used during re-oxygenation after hypoxia or anoxia to study neuronal recovery. Both groups of neurons showed a greater response to anoxia than hypoxia in terms of membrane potential (Vm) and input resistance (Rm). When the two groups were compared at each level of O2, XII depolarized more and in a shorter period of time than NCX. During anoxia, XII neurons responded with anoxic depolarization (AD) of > 20 mV/min by 3 min, along with a large decrease in Rm. NCX neurons, on the other hand, exhibited AD after a mean latency of approximately 9 min and 18% of NCX neurons did not even show AD. Although all neurons (both XII and NCX) recovered when re-oxygenated before or at AD, XII neurons failed to recover from periods of anoxia that were well tolerated by NCX neurons. We conclude that: (1) there are marked differences in the magnitude and trajectory of membrane depolarization between XII and NCX neurons in response to O2 deprivation, with NCX neurons showing a much longer latency to AD during anoxia than XII; and (2), when exposed to periods of anoxia of similar duration and severity, XII neurons are less likely to recover than NCX neurons and XII neurons may, therefore, be inherently more vulnerable to anoxia-induced injury than NCX neurons.