Background: Postural Orthostatic Tachycardia Syndrome (POTS) causes excessive heart rate and orthostatic intolerance on standing. About 25% patients have refractory POTS. Saline infusions reduce improve quality of life in such patients. Intravenous albumin expands circulatory volume by increasing plasma oncotic pressure. Efficacy of albumin infusions in POTS has not been studied. Methods: To assess the efficacy of albumin infusions in refractory POTS we treated patients with weekly or biweekly intravenous infusions of either 5% albumin in normal saline (n=16) or normal saline alone (n=7) in this open label comparative study. Most patients had failed multiple treatments. Serial clinical evaluations with individual symptom scores were the primary outcome measure of efficacy. Results: Mean follow up was 2 years (range 4 weeks - 5 years). 14/16 patients on albumin and 4/7 patients on saline infusions improved. Significantly more patients (7 vs. 1) on albumin showed marked improvement from baseline with more prominent reduction in orthostatic heart rate (mean reduction 19 vs. 14 beats minute). Albumin was well tolerated. More patients on saline (3/7 vs. 2/16) discontinued infusions due to lack of efficacy. Some patients required a permanent venous catheter. Conclusions: Intravenous albumin infusions are well tolerated and more effective than normal saline in refractory POTS.