Research in multiple sclerosis (MS) has recently been focusing on the extent of neuroaxonal damage and its contribution to disease outcome. In the present study, we examined spinal cord tissue from 30 clinically well-characterized MS patients. MS, amyotrophic lateral sclerosis (ALS), and control spinal cord tissue were subjected to morphometric analysis and immunohistochemistry for markers of cell damage and regeneration. Data were related to disease duration and age at death. Here, we present evidence for substantial, nonprogressive neuronal loss on the cervical and lumbar levels early in the disease course of MS. Chromatolytic neurons and immunoreactivity for c-Jun and GAP43 were observed in the ventral gray matter in and adjacent to actively demyelinating lesions, pointing toward neuronal damage and regeneration as an early response to lesion formation.