Diffuse axonal injury (DAI) is considered to be the morphological correlate of traumatic brain injury as seen in acceleration/deceleration trauma and is believed to be the main cause for a poor clinical outcome in the absence of detectable intracranial lesions. To estimate the overall incidence of DAI, and since most changes are only seen microscopically to rule out whether there is a high number of undetected cases, 450 non-selected human brains were examined. Samples from two brain areas (pons and cerebrum) were immunostained for beta-amyloid-precursor-protein (betaAPP), and axonal damage was assessed microscopically. Axonal injury was detected in 12% of all cases, but only one third had a history of traumatic brain injury. The majority of the positive cases were associated with drug intoxication, chiefly due to opiates. betaAPP staining was positive in both pons and cerebrum to a much higher extent in intoxication than in trauma cases; the latter showing axonal damage mainly in the pons area. This may reflect a more generalized pathomechanism in the intoxication group as compared to more biomechanical mechanisms in the trauma group. The findings also show that various causes may produce diffuse axonal injury and suggest that traumatic brain injury is not the only and probably not even the main cause of the observed neuropathological changes. A correlation between axonal damage and age-related processes could not be shown.