Orthostatic intolerance (OI) is common in teenagers (T) and young adults (A). Despite treatment with oral fluids, medication, and exercise, a significant number have symptoms from multiple organ systems and suffer low quality of life (QOL). Previous studies showed that acute intravenous (IV) hydration (IH) could help restore orthostatic tolerance; however, no data are available about the intermediate-term effects of IH. We therefore studied the efficacy of IH to improve QOL and manage medication-refractory OI patients. Our study population consisted of 39 patients (mean age = 16.1 ± 3.3) years; thirty-two were female. Average number of medications failed = 3.1. Average QOL score on self-reported OI questionnaire was 4.2 (normal QOL = 10). IV hydration consisted of normal saline (1–2 l/day, 3–7 days/week). 1) Orthostatic testing revealed Postural Orthostatic Tachycardia (24), Neurally Mediated Hypotension (14) or OI (1). 2) Average orthostatic change in heart rate was 48 ± 18 bpm. 3) IH was performed via intermittent IV access (10), PICC line (22), and Port (7). 4) Duration of IH varied from 1 week to 3.8 years (mean = 29 ± 47 weeks). 5) Overall, 79 % (n = 31) demonstrated clinically improved self-reported QOL. 6) Six patients who discontinued IH requested to restart treatment. (7) Complications consisted of upper extremity deep vein thrombosis (n = 3) and infection (n = 4). IH is an effective therapy to improve QOL in T&A with medication-resistant OI. Most patients continued to report improved QOL once IH was discontinued. IH should be considered a therapeutic option in medication-resistant OI patients with low QOL.