There is accumulating evidence that long-term disability and disease progression in multiple sclerosis (MS) are due to prolonged sodium channel opening along demyelinated axons. Despite good evidence in animal models of MS that partial voltage-gated sodium channel (VGSC) blockade reduces disease progression, little is known about its effects in patients, despite widespread use of such agents in the symptomatic management of MS.To determine if long-term exposure to the VGSC-blocking drug carbamazepine (CBZ) alters disease progression in MS.Using a retrospective chart review of patients diagnosed with MS, we compared progression of disability between patients exposed the VGSC blocker CBZ with those who were not exposed to the drug. Both whole-group and matched case-control analyses were performed after correcting for the influence of age, gender, MS subtype, expanded disability status score at diagnosis, use of disease-modifying therapy, and year of initial therapy. The multiple sclerosis severity scale (MSSS) was used as a measure of disease severity. The primary outcome measure was MSSS score difference between groups.Four hundred patients were included; 51 received CBZ symptomatic therapy (average duration of therapy 27 months). There was no significant difference in mean MSSS between the two groups in either the whole group comparison (p = 0.63) or the matched analysis (p = 0.12).Despite preclinical evidence suggesting a neuroprotective role of VGSC blockers in animal models of MS, this retrospective study suggests that long-term exposure to the VGSC-blocking drug CBZ fails to alter long-term disability and disease progression in MS patients.