To determine whether low ventricular filling pressures are a clinically relevant etiology of unexplained dyspnea on exertion, a database of 619 consecutive, clinically indicated invasive cardiopulmonary exercise tests (iCPETs) was reviewed to identify patients with low maximum aerobic capacity (VO2max) due to inadequate peak cardiac output (Qtmax) with normal biventricular ejection fractions and without pulmonary hypertension (impaired: n = 49, VO2max = 53% predicted [interquartile range (IQR): 47%-64%], Qtmax = 72% predicted [62%-76%]). These were compared to patients with a normal exercise response (normal: n = 28, VO2max = 86% predicted [84%-97%], Qtmax = 108% predicted [97%-115%]). Before exercise, all patients received up to 2 L of intravenous normal saline to target an upright pulmonary capillary wedge pressure (PCWP) of $>$/=5 mmHg. Despite this treatment, biventricular filling pressures at peak exercise were lower in the impaired group than in the normal group (right atrial pressure [RAP]: 6 [IQR: 5-8] vs. 9 [7-10] mmHg, P = 0.004; PCWP: 12 [10-16] vs. 17 [14-19] mmHg, P $<$ 0.001), associated with decreased stroke volume (SV) augmentation with exercise (+13 ± 10 [standard deviation (SD)] vs. +18 ± 10 mL/m(2), P = 0.014). A review of hemodynamic data from 23 patients with low RAP on an initial iCPET who underwent a second iCPET after saline infusion (2.0 ± 0.5 L) demonstrated that 16 of 23 patients responded with increases in Qtmax ([+24% predicted [IQR: 14%-34%]), VO2max (+10% predicted [7%-12%]), and maximum SV (+26% ± 17% [SD]). These data suggest that inadequate ventricular filling related to low venous pressure is a clinically relevant cause of exercise intolerance.