ABSTRACT Fracture-dislocation is one of the most common causes of spinal cord injury (SCI) in human adults, yet it is not widely studied experimentally. Clinical studies have found that anterior fracture-dislocation occurs more commonly and produces greater neurological deficit than lateral fracture-dislocation. However, the effect of loading direction on SCI neuropathology has not been investigated experimentally and the reasons behind these clinical differences are not known. Thoracolumbar vertebrae T12-L1 of anaesthetized rats were dislocated anteriorly or laterally by 9 mm at 220 mm/sec. Spinal cord sections from animals euthanized at 1, 3, and 6 h post-injury, were stained with hematoxylin and eosin (H&E) to detect hemorrhage, the pathologic accumulation of beta-amyloid precursor protein (betaAPP) in white matter axons, and degenerating neurons (Fluoro-Jade and loss of NeuN) in the gray matter. The vertebral fracture load and maximum load were similar for both directions of dislocation; however, vertebral fracture occurred at 4.3 mm (+/-1.5 mm SD) during anterior dislocation compared to 1.1 mm (+/-0.7 mm SD) during lateral dislocation (p < 0.001). betaAPP accumulation and reduction of NeuN immunoreactivity (IR) were greatest along a diagonal band across the spinal cord angled at 45 degrees to the direction of loading (in different planes for each loading direction). Hemorrhage volume (p < 0.05), betaAPP-IR, and reduction of NeuN-IR (p < 0.05 in ventral horns) were more pronounced following anterior dislocation. In addition, there was a different spatial distribution of axonal damage for each direction of dislocation. The findings of this study may explain the greater severity of anterior fracture-dislocation observed clinically and reinforces the need to experimentally model differing human SCIs.