Periventricular leukomalacia (PVL) is a major neuropathological substrate in cerebral palsy. PVL is multifactorial. In previous studies, we and others showed that a cytokinemediated immune-inflammatory mechanism involving particularly tumor necrosis factor (TNF)-โฃ is implicated in etiopathogenesis. The precise molecular pathway(s) leading to cell injury remains, however, unsettled. In this study, we conducted in situ immunohistochemical investigations and nucleic acid hybridization to further explore putative mediators involved in cell death mechanism(s). We studied 14 neonatal human brains neuropathologically confirmed for PVL and focused on a probable cytotoxic molecular cascade triggered by TNF-โฃ, involving TNF-โฃ receptor (TNF-โฃ R), nitric oxide synthase (NOS), and apoptosis in these white matter (WM) lesions. Expression of mainly TNF-โฃ R1 and to a lesser extent TNF-โฃ R2 was detected in PVL in more than one cell type in and around WM lesions. In addition, positively stained NOS cells in the deep WM also were observed in these lesions. Focally, apoptotic cells were identified, sometimes in high concentrations in the WM lesions at different stages of evolution. These molecular, immune, and apoptotic markers often were noticed on various glial cell types including oligodendrocytes, and on inflammatory cells particularly monocyte/macrophages. These findings suggest that apoptotic cell death that we detected in PVL might result from high NOS activity triggered by TNF-โฃ action and mediated by its receptor (TNF-โฃ R1). These results could open new horizons for preventive approaches.