There is increasing interest in the contribution that axonal damage may make to clinical disability in multiple sclerosis (MS). The present study reports a post-mortem examination of the area occupied by the lateral white matter columns of the spinal cord and nerve fibre density in the corticospinal tracts at C3 and T2 in 23 males and 20 females with MS, who lacked plaques at these levels, and in 31 controls who, although most had had some neurological disease, showed no sign of cervical or spinal cord thoracic disease. The lateral column cross-sectional area, measured by low power image analysis of the outlined lateral columns, was reduced in MS by 17% at C3 and 21% at T2 in males and by 13% at C3 and 18% at T2 in females. These reductions were significant at both levels in males (P<0.004 at C3 and P<0.009 at T2 ) but only at T2 in females (P<0.03). The nerve fibre density, measured by automatic image analysis of ×200 microscopic fields in the region occupied by the crossed pyramidal tracts, was reduced by 41% at C3 and 42% at T2 in males and by 19% at both C3 and T2 in females. These reductions were likewise significant at both levels in males (P<0.003 and P<0.000 at C3 and T2 , respectively) and T2 only in females (P<0.045). In MS, nerve fibre density was significantly lower at C3 (P<0.004) and T2 (P<0.000) in males than females. No differences were seen in these parameters between males and females in controls. The reductions in total nerve fibre densities were entirely accounted for by reductions in small nerve fibres (cross sectional area less than 5 μm2 ). No significant reductions were seen in large fibre (cross sectional area 5 μm2 or more) densities. It is concluded that substantial axonal loss and spinal cord lateral column white matter atrophy occur at C3 and T2 in MS, and that these changes can be detected in some patients from early in the course of the disease.