Anemia is a common complication of autonomic failure and reduced red blood cell mass may contribute to the orthostatic hypotension of these patients. We investigated whether treatment with recombinant erythropoietin improves anemia and increases blood pressure in patients with primary autonomic failure. Three patients with multiple system atrophy and autonomic failure and one with pure autonomic failure were studied. All patients had normocytic normochromic anemia and low (n = 2) or normal (n = 2) serum levels of erythropoietin. Treatment with erythropoietin, 4000 U subcutaneously biweekly for 6 weeks, increased hematocrit and blood pressure in all patients. Hematocrit increased from 33.9 +/- 0.7 to 44.3 +/- 1.4%, blood pressure in supine position increased from 150 +/- 8/87 +/- 8 (systolic/diastolic; mean +/- SD) to 166 +/- 25/92 +/- 12 mmHg, and after 3 min in the head-up tilt position from 86 +/- 21/47 +/- 15 to 102 +/- 23/63 +/- 12 mmHg, (p < 0.05). All patients reported improvement in orthostatic symptoms and increased tolerance to standing. The study shows that treatment with erythropoietin improves anemia, increases blood pressure and ameliorates orthostatic hypotension in patients with primary autonomic failure.