Background: The modifiable risk factor exerting the most substantial influence on the development and disease course of multiple sclerosis (MS) is cigarette smoking. Furthermore, smoking is associated with a higher risk of suffering from one or more comorbidities and potentially contributes to polypharmacy. We aimed to use personality tests to explore health-promoting and harmful patient characteristics. Objective: To investigate two important factors influencing the course of MS – the degree of smoking dependence and the status of polypharmacy – in association with personality traits. Design: This is a bicentric, cross-sectional study. Methods: We collected sociodemographic, clinical and medical data from patients with MS ( n = 375) at two German neurological clinics. The participants were asked to complete the NEO Five-Factor Inventory (NEO-FFI) and the Temperament and Character Inventory-Revised (TCI-R). Relationships between variables were examined using correlation analyses, and differences between groups were examined using linear models. Current smokers with MS were also asked to complete the Fagerström questionnaire to categorize them into patients with mild, moderate and severe smoking dependence. Results: In our sample, 67.5% were women, and the mean age was 48.1 years. The patients had a median Expanded Disability Status Scale of 3.0 at a median disease duration of 10 years. Patients with MS with severe smoking dependence had on average a significantly higher neuroticism score in the NEO-FFI compared to those with mild or moderate smoking dependence. Patients with MS and polypharmacy had significantly higher neuroticism scores than those without. In the extraversion scale of the NEO-FFI, patients with MS and polypharmacy had significantly lower scores on average. Significant differences were also found when analysing the TCI-R in patients with MS and heavy smoking dependence, with higher scores for harm avoidance (HA) and lower scores for reward dependence, self-directedness (S-D) and cooperativeness (CO) in various subscales. Polypharmacy in patients with MS was associated with higher scores for HA and self-transcendence. Furthermore, patients with polypharmacy showed lower values than patients without polypharmacy in individual subscales of the dimensions of persistence, S-D and CO. Conclusion: Using the NEO-FFI, we were able to show that neuroticism is a detrimental trait and extraversion a protective trait in patients with MS in relation to nicotine dependence and polypharmacy. In addition, the evaluation of the TCI-R showed that high HA as well as low S-D and CO scores were more common in patients with MS and nicotine dependence or polypharmacy. With this knowledge, the risk of polypharmacy and smoking can be understood in the context of personality characteristics and targeted treatment and counselling can be provided.