AbstractPerinatal hypoxia–ischemia (HI) occurs in 0.2%–0.4% of all live births, with 100% O2 resuscitation (HHI) remaining a standard clinical treatment. HI produces a broad spectrum of neuronal death phenotypes ranging from a more noninflammatory apoptotic death to a more inflammatory necrotic cell death that may be responsible for the broad spectrum of reported dysfunctional outcomes. However, the mechanisms that would account for this phenotypic spectrum of cell death are not fully understood. Here, we provide evidence that Bcl‐2‐associated X protein (Bax) can shuttle to different subcellular compartments in response to HI, thus triggering the different organelle‐associated cell death signaling cascades resulting in cell death phenotype diversity. There was an early increase in intranuclear and total nuclear Bax protein levels followed by a later Bax redistribution to the mitochondria and endoplasmic reticulum (ER). Associated with the organelle‐specific Bax shuttling time course, there was an increase in nuclear phosphorylated p53, cytosolic cleaved caspase‐3, and caspase‐12. When HI‐treated P7 rats were resuscitated with 100% O2 (HHI), there were increased lesion volumes as determined by T2‐weighted magnetic resonance imaging with no change in cortical apoptotic signaling compared with HI treatment alone. There was, however, increased inflammatory (cytosolic‐cleaved interleukin‐1β) and necrotic (increased nuclear 55‐kDa‐cleaved PARP‐1 [poly‐ADP‐ribose 1] and decreased nuclear HMGB1 [nuclear high‐mobility group box 1]) after HHI. Furthermore, HHI increased ER calpain activation and ER Bax protein levels compared with HI alone. These data suggest that 100% O2 resuscitation increases Bax‐mediated activation of ER cell death signaling, inflammation, and lesion volume by increasing necrotic‐like cell death. In light of these findings, the use of 100% O2 treatment for neonatal HI should be reevaluated. © 2008 Wiley‐Liss, Inc.