Background: Autonomic dysfunction is frequently observed in patients with multiple sclerosis (MS) but the evolution over time and the relationship to clinical characteristics are not yet established. Objectives: We investigated the correlation of disease activity and progression of disability with composite scores of cardiovascular autonomic dysfunction and serum levels of catecholamines in a cross-sectional study of patients with clinically active and clinically stable MS. In a longitudinal study of clinically active MS patients, we performed cardiovascular reflex tests for up to 2 years. Methods: Twenty-six patients with clinically active relapsing-remitting MS, age 33.0+7.3 years, and nine patients with clinically stable MS, age 41.3+10.9 were studied. Twenty-four healthy volunteers served as controls. Standard autonomic tests were repeated at 3, 6, 12, 18 and 24 months in 18 of the 26 active patients participating in a placebo-controlled trial with interferon-b-1a. Parasympathetic dysfunction was assessed by heart rate response to the Valsalva manoeuvre, deep breathing and active change of posture, while sympathetic dysfunction was analysed by blood pressure response to active change of posture and to sustained handgrip, and by measuring levels of norepinephrine and epinephrine in serum obtained in the supine position. Results: In the cross-sectional study, the number of patients with at least one abnormal sympathetic test was higher in the `active' patient group (39%) than in healthy controls (8%, P50.02) or `stable' patients (0%, P50.04), while no difference was seen in the parasympathetic score. Median catecholamine levels were significantly lower in `active' MS patients than in those with stable disease (norepinephrine, 204 ng/l (interquartile range 158-310 ng/l) vs 363 ng/l (269-507 ng/l), P50.02 and epinephrine, 23 ng/l (16-28 ng/l) vs 32 ng/l (24-107 ng/l), P50.04). In the subgroup of patients studied longitudinally, parasympathetic but not sympathetic dysfunction increased slightly during the follow-up period, with a significant correlation to the increase in clinical disability (r=0.7, P50.002). No difference was seen for any of the autonomic scores between patients treated with interferon-b (n=12) and those receiving placebo (n=6). During acute exacerbations, only parasympathetic dysfunction tended to increase in parallel with a deterioration in the EDSS. Conclusions: Parasympathetic dysfunction was closely related to the progression of disability in patients with MS. In contrast, sympathetic dysfunction was associated to the clinical activity of MS. This is in line with previous observations suggesting that the autonomic nervous system may be intimately linked with the disordered immune regulation in MS.