Background. Previous reports suggest that inflammatory bowel diseases may be accompanied by abnormalities in the neural autonomic profile. We tested the hypotheses that 1. an exaggerated sympathetic activity characterizes active ulcerative colitis (UC) 2. a reduction of sympathetic activity by clonidine would be associated with clinical changes of UC. Methods. In 23 patients with UC and 20 controls, muscle sympathetic nerve activity (MSNA), ECG, blood pressure and respiration were continuously recorded and plasma catecholamine evaluated, both at rest and during a 75° head-up tilt. Autonomic profile was assessed by MSNA, norepinephrine, epinephrine, spectral markers of cardiac sympathetic (LF_RR n.u., normalized units) and parasympathetic (HF_RR , n.u.) modulation and sympathetic vasomotor control (LF_SAP), obtained by spectrum analysis of R-R and systolic pressure variability. Among UC patients, 16 agreed to be randomly assigned to 8 weeks transdermal clonidine (15 mg/week, 9 subjects), or placebo (7 patients). Autonomic profile, Disease Activity Index (DAI) and endoscopic pattern were compared before and after clonidine/placebo. Results. At rest, MSNA, heart rate (HR), LF_RR, LF/HF and LF_SAP were higher and HF_RR was lower in patients than in controls. Tilt decreased HF_RR and increased MSNA and LF_RR . less in patients than in controls. Clonidine decreased HR, MSNA, epinephrine, LF_RR and increased HF_RR , whereas placebo had no effects. Changes of the autonomic profile after clonidine were associated with reduction of DAI score. Conclusions. An overall increase of sympathetic activity characterized active UC. Normalization of the autonomic profile by clonidine was accompanied by an improvement of the disease.