Pontosubicular neuron necrosis (PSN) represents an age-specific response to severe hypoxic-ischemic injury occurring in human neonates but not in older children or adults. Histologically, PSN is characterized by acute neuronal death in the pontine nuclei and the hippocampal subiculum bearing the hallmarks of apoptosis. In animal models of hypoxic-ischemic injury, induction of neuronal apoptosis can be triggered by Fas (CD95/Apo-1), a cell surface receptor of the tumor necrosis factor-alpha superfamily, which transduces apoptotic death signals when cross-linked by its natural ligand. Here, we have investigated the expression of Fas/Fas ligand in human autopsy material consisting of 13 PSN cases and 10 age-matched cases without PSN. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, immunohistochemistry, and double labeling for Fas/Fas ligand and the astrocyte marker glial fibrillary acid protein, the microglia/macrophage specific marker KiM1P, and the neuronal marker NeuN were performed on formalin-fixed brain specimens. Although mainly neurons of both PSN and controls expressed Fas receptor, expression was significantly increased (p = 0.001) in PSN cases in which predominantly degenerating cells with signs of early apoptosis showed Fas expression. In contrast, Fas ligand expression was found mainly on astrocytes and microglial cells. There was no significant difference between cases with and without PSN. We conclude that in the developing human brain, cells expressing the Fas receptor may be susceptible to undergoing apoptosis in response to hypoxic-ischemic injury.