The neuropathologist involved in forensic work is not uncommonly confronted with a case in which there is no or only a limited history or, if available, the information is uncertain or is often conflicting. In recent years the immunohistochemical stain β-amyloid precursor protein (β-APP) has been used to assess the extent of axonal injury in a variety of pathological processes but in forensic practice is of greatest utility in the assessment of traumatic brain injury. Diffuse traumatic axonal injury (TAI) in humans has been demonstrated by β-APP immunoreactivity in patients surviving at least 2 h after head injury. However, many of these patients also have an associated ischaemic injury, either focal or diffuse, which may make the interpretation of β-APP immunoreactivity difficult. The present study was designed to evaluate if the published descriptions of the different morphological patterns and distributions of β-APP immunoreactive axons could be used to microscopically distinguish axonal injury attributed to trauma from other causes. To test this hypothesis a total of 73 cases were reviewed. The cases were selected from six different groups based on clinical information. Immunostained sections from each case were assessed ‘blind’ to the clinical history, and the microscopic pattern and distribution of β-APP positive axons were recorded. Haematoxylin and eosin (H+E) stained sections were then reviewed for each case and a final pathological diagnosis was recorded and compared to the clinical history. 62/73 (85%) cases were correctly correlated with the clinical history and in particular 14/17 (82%) cases of TAI were correctly identified. These findings indicate that the published microscopic patterns of the distribution of β-APP positive axons in TAI and in diffuse ischaemic injury can be used, in conjunction with microscopy of H+E stained sections to determine the cause of axonal pathology in most cases.