We tested the hypothesis that the oral -1 adrenergic agonist, midodrine, would limit the fall in arterial pressure observed during exercise in patients with pure autonomic failure (PAF). 14 subjects with PAF underwent a stand test, incremental supine cycling exercise (25, 50, 75 W), and ischemic calf exercise, before (control) and one hour after ingesting 10 mg midodrine. Heart rate (HR, ECG), beat-to-beat blood pressure (MAP, arterial catheter), cardiac output (Q, open-circuit acetylene breathing), forearm blood flow (FBF, doppler ultrasound), and calf blood flow (CBF, venous occlusion plethysmography) were measured. The fall in MAP after standing for 2 min was similar (~60 mm Hg, p = 0.62). Supine MAP immediately before cycling was greater after midodrine (124±6 vs 117±6 mm Hg, p < 0.03), but cycling caused a workload-dependent hypotension (p < 0.001) while increases in Q were modest but similar. Midodrine increased MAP and total peripheral resistance (TPR) during exercise (p < 0.04), but the exercise-induced fall in MAP and TPR were similar during control and midodrine (p = 0.27 and 0.14). FBF during cycling was not significantly reduced by midodrine (p > 0.2). By contrast, recovery of MAP -after cycling was faster (p < 0.04) after midodrine (~25 mmHg higher after 5 minutes). Ischemic calf exercise evoked similar peak CBF in both trials, but midodrine reduced the hyperemic response over five minutes of recovery (p < 0.02). We conclude midodrine improves blood pressure and TPR during exercise and dramatically improves the recovery of MAP after exercise.