© 2017 van Riel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: We recently reported a novel observation that many patients with equal resting supine right ventricular(RV) and pulmonary artery(PA) systolic pressures develop an RV outflow tract (RVOT) pressure gradient during upright exercise. The current work details the characteristics of patients who develop such an RVOT gradient. Methods: We studied 294 patients (59.7±15.5 years-old, 49% male) referred for clinical invasive cardiopulmonary exercise testing, who did not have a resting RVOT pressure gradient defined by the simultaneously measured peak-to-peak difference between RV and PA systolic pressures. Results: The magnitude of RVOT gradient did not correspond to clinical or hemodynamic findings suggestive of right heart failure; rather, higher gradients were associated with favorable exercise findings. The presence of a high peak RVOT gradient (90th percentile, 33mmHg) was associated with male sex (70 vs. 46%, p = 0.01), younger age (43.6±17.7 vs. 61.8±13.9 years, p<0.001), lower peak right atrial pressure (5 [3–7] vs. 8 [4–12]mmHg, p<0.001), higher peak heart rate (159±19 vs. 124±26 beats per minute, p<0.001), and higher peak cardiac index (8.3±2.3 vs. 5.7±1.9 L/min/m2, p<0.001). These associations persisted when treating peak RVOT as a continuous variable and after age and sex adjustment. At peak exercise, patients with a high exercise RVOT gradient had both higher RV systolic pressure (78±11 vs. 66±17 mmHg, p<0.001) and lower PA systolic pressure (34±8 vs. 50±19 mmHg, p<0.001). Conclusions: Development of a systolic RV-PA pressure gradient during upright exercise is not associated with an adverse hemodynamic exercise response and may represent a normal physiologic finding in aerobically fit young people.