In multiple system atrophy (MSA), increased venous compliance with excessive venous pooling is assumed to be a major contributor to orthostatic hypotension (OH); however, venous compliance has never been assessed in patients with MSA. We evaluate the severity and distribution of adrenergic, cardiovagal, and sudomotor failure in 11 patients with probable MSA (MSA-P), 14 age- and gender-matched control subjects and 8 patients with Parkinson’s disease (PD) but not OH. Calf venous compliance as well as venous filling and capillary filtration were measured using calf plethysmography. Response to directly acting -adrenergic stimulation (10 mg midodrine) on calf venous compliance was additionally evaluated. Contrary to our hypothesis, pressure-volume curves in the legs of MSA patients were flatter than in PD (P<0.05) patients or controls (P<0.001), this indicated reduced calf venous compliance in MSA. The MSA group had reduced venous filling compared to controls (P<0.001) or PD (P<0.001) but normal capillary filtration rate (P=0.73). Direct &#945;-adrenergic stimulation resulted in a slight but significant reduction of calf venous compliance in controls (P=0.001) and PD (P<0.001) but not in the MSA group. The compliance change in MSA significantly regressed with autonomic failure (composite autonomic severity scale - CASS, r²=0.56) but not with parkinsonism (UMSARS, r²=0.12). Our data indicate that MSA patients with chronic OH have reduced, rather than increased, venous compliance in the lower leg. We postulate that chronic venous distension that is associated with OH results in structural remodelling of veins, leading to reduced compliance, a change which may protect patients against orthostatic stress.