Background: In persons with Multiple Sclerosis (PwMS) cardiorespiratory fitness has been associated with disease severity, walking capacity and comorbidities. However, current evidence is of moderate quality and a large-scale single-center study is needed to further elucidate these relationships Objective: The purpose of the study was 1) to examine the relationship between cardiorespiratory fitness and disease severity in PwMS; 2) to investigate the relationship between cardiorespiratory fitness and walking speed and comorbidities; and 3) to examine the potential impact of Multiple Sclerosis (MS) disease type on these relationships Methods: Data was collected from a database consisting of data from 700 inpatients at Valens Rehabilitation Center, Switzerland. VO ₂ peak (cardiorespiratory fitness), information on disease course and MS type, walking performance, comorbidities and anthropometric was eligible from 242 PwMS. Results: Cardiorespiratory fitness and Expanded Disability Status Scale (EDSS) was inversely related (r = −0.465, p <.01). A multiple linear regression analysis showed that an increase of 1 point on the EDSS score was associated with a decrease of 1.88 mL kg ⁻¹ min ⁻¹ and explained 36% of the variance, when adjusted for time since diagnosis, gender, age, and MS type. Walking speed and cardiorespiratory fitness was significantly correlated (r = 0.584, p <.01) and the relapse remitting MS (RRMS) group (1.12 ± 0.42 m/s) walked significantly faster than the secondary progressive MS (SPMS) group (0.91 ± 0.37 m/s) p <.05, but the difference was non-significant when adjusted for age, p =.429. Conclusion: The present study shows that 1) an increase of 1 EDSS point is associated with a decrease of 1.88 mL kg ⁻¹ min ⁻¹ when adjusted for time since diagnosis, gender, age and MS type, 2) cardiorespiratory fitness and walking speed was significantly related but only minimally affected by MS type, and 3) hypertension is associated with a lower cardiorespiratory fitness level.