Eleven patients with orthostatic intolerance had, for no detectable reason, a marked reduction in blood volume (73 +/- 2.29% [SE] of normal). Head-up tilt caused a pronounced increase in heart rate (+ 39 +/- 6 beats/min); one patient had a vasovagal episode after the initial tachycardia. Extensive diagnostic study excluded pheochromocytoma, hypoaldosteronism, or any obvious cause for hypovolemia (total plasma catecholamines, 372 +/- 53 ng/L; plasma aldosterone level, 14.5 +/- 2.56 ng/100 mL; plasma cortisol level, 18.5 +/- 2.4 ng/100 mL). The supine hemodynamic pattern (decreased cardiac output and increased total peripheral resistance with normal ejection fraction and mean transit time) was markedly different from that of hyperbeta adrenergic states. Acute plasma volume expansion (+ 11 +/- 2%) in ten patients using human serum albumin improved both their symptoms and heart rate response to tilt. After long-term blood volume expansion with florinef (E.R. Squibb, Princeton, New Jersey), 0.1 mg twice a day, and a high-salt diet, the head-up tilt test was repeated in five patients. The response was normal in four patients. These observations outline a syndrome of marked idiopathic hypovolemia with symptomatic labile hypertension and intolerance to head-up tilt, alleviated by volume expansion.