ABSTRACT Primary autonomic failure is a group of rare neurodegenerative disorders that primarily affect the autonomic nervous system. These patients develop neurogenic orthostatic hypotension (OH) because of impaired autonomic reflexes that control cardiovascular and neuro-humoral adaptation to upright posture. The treatment of neurogenic OH is challenging; the therapeutic options are scarce, and some patients are refractory to treatment. Our preliminary results showed that 36% of patients with primary autonomic failure did not improve OH-related symptoms and upright blood pressure with midodrine, the current standard of care. The use of midodrine is limited in some patients by the development of side effects such as pilomotor reactions, pruritus of the scalp, urinary retention, and supine hypertension. Other available therapies include the recent FDA approved drug, droxidopa, a synthetic norepinephrine precursor; however, the long-term efficacy and safety of this medication is still unknown. Hence, there is an urgent need to identify new pharmacotherapies for the treatment of neurogenic OH in primary autonomic failure. Atomoxetine is a selective norepinephrine transporter inhibitor that increases the availability of norepinephrine in the synapse by blocking its reuptake. This medication is currently approved for the treatment of attention-deficit hyperactivity disorder (ADHD) in the United States, and seven million people with ADHD chronically use atomoxetine or similar drugs. Our preliminary data in sixty-five patients with primary autonomic failure and neurogenic OH showed that atomoxetine was more effective than midodrine in improving standing SBP (+7.5 mm Hg). Notably, only atomoxetine and not midodrine induced a significant reduction in OH-related symptoms (lightheadedness and dizziness) compared with placebo. The response to an acute administration of a pressor agent does not predict long-term efficacy of the drug. In this proposal, we will test the hypothesis that prolonged administration of the norepinephrine transporter blocker, atomoxetine, improves OH-related symptoms and OH-impact on daily activities compared with placebo in primary autonomic failure. We propose a randomized, double-blind, placebo- controlled, crossover study.