Postural tachycardia syndrome (POTS) is characterized by excessive increases in heart rate (HR) upon standing. Previous studies have shown that standing HR decreases over time in POTS patients given placebo. We hypothesized that this reduction is due to cardiovascular physiological alteration, as opposed to psychological benefit from perceived therapy. To prospectively test this hypothesis, we examined the effects of an open-label “No Treatment” intervention (NoRx) compared to a patient-blinded placebo on standing HR in POTS patients. Twenty-one POTS patients participated in a randomized, crossover trial with oral placebo versus NoRx administered at 9 AM. Seated blood pressure (BP) and HR were measured at baseline and every hour for 4 hours (h). Similarly, BP and HR were measured while patients stood for 10 minutes at these time points. Standing HR significantly decreased over time with both NoRx (baseline: 112 ± 13 bpm, 4h: 103 ± 16 bpm) and placebo (baseline: 112 ± 14 bpm, 4h: 102 ± 16 bpm; Ptime<0.001), but this effect was not different between interventions (Pdrug=0.771). POTS patients have exaggerated orthostatic tachycardia in the morning that decreases over time with either placebo or NoRx interventions, suggesting this phenomenon is due to cardiovascular physiologic variation. These data highlight the need for a placebo arm in hemodynamic clinical trials in POTS, and may have important implications for diagnosis of these patients. This article is protected by copyright. All rights reserved.