The therapeutic efficacy of midodrine, an alpha-adrenergic agonist that does not cross the blood-brain barrier, was investigated in a double-blind crossover trial in seven patients with orthostatic hypotension due to autonomic failure. We identified two groups of patients: those in whom upright mean arterial pressure significantly increased (group I, n = 3) and those in whom upright mean arterial pressure decreased (group II, n = 4) during midodrine treatment. Body weight changed in a parallel manner with upright blood pressure, increasing in patients of group I and decreasing in patients of group II (p < 0.05). Autonomic cardiovascular reflexes were significantly more impaired in patients of group II than in patients of group I. We conclude that midodrine is effective in the treatment of orthostatic hypotension only in those patients with significant preservation of autonomic reflexes. Conversely, in patients with markedly impaired baroreceptor mechanisms, treatment with midodrine may produce extracellular fluid volume depletion and exacerbate orthostatic hypotension.