We tested the independent utility of β-amyloid precursor protein (β-APP) immunohistochemical staining as evidence of brain trauma in the deaths of young children. Blinded reviewers retrospectively reviewed immunostained brain tissues from homicidal deaths, age-matched control cases without evidence of trauma, as well as cases of sudden infant death syndrome (SIDS). The reviewers correctly identified five of the seven cases with documented inflicted head trauma. However, one of seven age-matched control cases and one of 10 SIDS/sudden unexplained death in infancy (SUDI) cases demonstrated staining patterns similar to those seen in cases of inflicted trauma. We discuss these cases and the circumstances surrounding them with the intent to explain the difficulties associated with immunohistological interpretation of axonal injury. Although the utility of β-APP is quite powerful if not confounded by global hypoxic-ischemic injury, ultimately, β-APP studies should be only one piece of information in the determination of cause and manner of death.