Objective: As personality changes and personality disorders are frequently observed in multiple sclerosis (MS), personality may be a prognostic factor for this disease. The present study investigated the influence of personality on disability, progression, and treatment adherence in MS.

Method: Personality was assessed in 41 patients with Relapsing–Remitting MS (30 females; mean age = 42.63 years) using the NEO Personality Inventory—3rd edition. Disability was measured with the Expanded Disability Status Scale, and treatment adherence information was collected from the Swiss MS Cohort. Correlation, multiple linear and partial least square regressions were performed to examine relations between personality, disability, and treatment adherence in MS.

Results: After accounting for age and time since disease onset, our analysis revealed that Neuroticism (β = 0.32, p = 0.01) and its Vulnerability facet (β = 0.28, p < 0.05) predicted greater disability, whereas Extraversion (β = −0.25, p = 0.04) and its Activity facet (β = −0.23, p < 0.05) predicted milder disability. Regarding disability progression, correlational analysis revealed that it was negatively correlated with Extraversion (r = −0.44, p = 0.02) and the Feelings facet of Openness (r = −0.41, p = 0.03), but regressions failed to highlight any predictive links. No significant results could be demonstrated for treatment adherence.

Conclusions: Overall, our study showed that some personality traits can impact disability in MS, indicating that these should be considered in clinical practice, as they could be used to adapt and improve patients’ clinical support.