OBJECTIVES: This study evaluates cardiovascular autonomic dysfunction (CAD) in multiple sclerosis (MS) and explores if CAD is related to clinical outcomes and fatigue severity. METHODS: A total of 53 MS patients (30 relapsing-remitting, RRMS; 23 progressive, PMS) and 30 healthy controls were evaluated. TaskForce® Monitor was used to assess impedance cardiography parameters, heart rate (HRV), and blood pressure (BPV) variability during head-up tilt test (HUTT). Expiration/inspiration (E/I) ratio was assessed in response to a deep breathing test. Fatigue severity was evaluated using Chalder Fatigue Scale (CFQ). RESULTS: Compared to controls, PMS patients were characterized by increased sympathetic-parasympathetic ratio at rest (p < 0.01), decreased resting values of parasympathetic parameters (high-frequency HRV, p < 0.05; E/I ratio, p < 0.001), and index of contractility (p < 0.05), whereas RRMS patients showed reduced E/I ratio (p < 0.01). Compared to RRMS group, PMS patients had higher sympathovagal ratio and lower cardiac inotropy parameters (p < 0.05). No intergroup differences were observed for cardiovascular and autonomic function test parameters after HUTT. PMS and low CFQ physical score were identified as independent predictors of sympathetic hyper-reactivity as measured with HRV. Greater disability and male sex were predictors of diastolic BP increase and reduced cardiac inotropy parameters, and older age was predictor of decreased vagal tone (E/I ratio, high-frequency HRV). CONCLUSION: Cardiovascular autonomic modulation is altered in MS and highly dependent on disease variant, disability level, fatigue severity, and patients' demographics.