Disability in multiple sclerosis (MS) is considered primarily a result of axonal loss. However, correlation with spinal cord cross-sectional area—a predictor of disability—is poor, questioning the unique role of axonal loss. We investigated the degree of synaptic loss in postmortem spinal cords (18 chronic MS, 8 healthy controls) using immunohistochemistry for synaptophysin and synapsin. Substantial (58–96%) loss of synapses throughout the spinal cord was detected, along with moderate (47%) loss of anterior horn neurons, notably in demyelinating MS lesions. We conclude that synaptic loss is significant in chronic MS, likely contributing to disability accrual. ANN NEUROL 2020;88:619–625.