Immunohistochemical staining for beta-amyloid precursor protein (betaAPP) has been validated as a marker for axonal injury in adults surviving > or = 2 hours after white matter damage. The significance of betaAPP staining in pediatric brains and spinal cords is not as well established. We evaluated the white matter immunoreactivity for betaAPP from a variety of pediatric medicolegal autopsies: natural disease (non-Sudden Infant Death Syndrome [SIDS]), SIDS, motor vehicle accidents, drowning, near-drowning, overlay, carbon monoxide toxicity, miscellaneous trauma, and mechanical asphyxia. The cases of carbon monoxide toxicity, motor vehicle accidents (death at scene), drowning (with resuscitation), and a natural (non-SIDS) death had no significant white matter staining. The traumatic deaths with a significant survival interval, a variety of natural deaths, the near-drowning case, and surprisingly, all SIDS had detectable betaAPP white matter immunostaining. These results demonstrate that features other than traumatic axonal injury, such as metabolic insults and hypoxic-ischemic injury secondary to vascular compromise, must contribute to betaAPP immunostaining. In addition, we describe a variety of betaAPP-immunoreactive structures not previously reported in the pediatric population. This study illustrates that betaAPP immunostaining enhances detection of a variety of white matter changes, and provides a basis for interpretation of these results.