Objective To investigate the effects of anti-epileptic drugs (AED) on the overall burden of disease in patients with neuro-autoimmune disease (NAD). Background AEDs have shown to provide benefits against neurological damage in patients with various neurological illnesses. However, the extent of AEDs role in neuroprotection and the prevention of additional comorbidity in patients with NAD has not been completely characterized. Design/Methods A retrospective analysis on 34464 patients hospitalized at a tertiary care center in a major metropolitan area was conducted. 3997 patients were on AED medications, while 30467 patients were not taking any AEDs (nAED). 190 patients had a NAD diagnosis. Patients with NAD were classified according to use of AED or nAED (aAED and anAED). The outcomes compared included prevalence of neurological complications defined as either seizure, blurry vision, delirium, or altered mental status, encephalopathy, length of stay, ICU admission, comorbidity, and death. Results There was no significant difference in the prevalence of NAD between patients in AED or nAED (0.75%, 0.52%, p > 0.05). Among patients with aAED and anAED, there was no significant difference in length of stay (8.7, 7.8, p > 0.5), ICU admission (26.7%, 12.5%, p > 0.05), prevalence of comorbidities (56.7%, 52.5%, p > 0.05), or mortality (6.7%, 3.1%, p > 0.3). 36% of aAED and 16.3% of anAED had high risk comorbidity (p < 0.05). The prevalence of overall neurological complications was 37% and 10% among aAED and anAED, respectively (p < 0.001). Patients in aAED had significantly higher encephalopathy compared to anAED at 23% and 3.8%, respectively (p < 0.0001). Conclusions These results suggest that AEDs may be associated with an increase in high-risk comorbidities and neurological complications including encephalopathy among patients with NAD. Work is in progress to assess the contribution of the primary diagnoses for which AEDs were prescribed on the burden of NAD.