Background: Initial orthostatic hypotension (IOH) is a common form of orthostatic intolerance defined by a large reduction in blood pressure (BP) within 15s of active standing resulting in symptoms of presyncope or a faint. Symptoms may occur numerous times within a single day, which significantly affects patients’ quality of life. However, there is limited data exploring IOH physiology and symptom management. Aims: We aimed to: (1) determine if the reflex underlying IOH had a refractory period; (2) better understand the physiology underlying IOH; (3) provide effective symptom management options; and (4) explore the patient experience living with IOH. Methods: A total of 26 participants enrolled in aims 1-3 and 16 in the fourth and final aim. Aims 1-3 involved series of randomized sit-to-stand maneuvers with and without interventions. Data are presented as mean±SD. Aim 4 consisted of one-on-one semi-structured interviews between the IOH participant and researcher probing into the patient experience living with IOH. Results: In aim 1, the drop in systolic BP (SBP) after standing was blunted following a short sit (-12±6 mmHg) compared to a long sit (-34±16 mmHg; p<0.001). In aim 2, the drops in SBP following the Serial 7 test (-26±12 mmHg; p=0.004), Cold Pressor test (-20±15 mmHg; p<0.001), and functional electrical stimulation (-28±12 mmHg; p=0.01) were significantly reduced compared to no intervention (-34±11 mmHg). In aim 3, the drop in SBP after standing was blunted following muscle pre-activation (-23±13 mmHg; p<0.001) and muscle post-tensing (-22±12 mmHg; p<0.001) compared to no intervention (-35±12 mmHg). In aim 4, an overriding theme was identified: Life, when simply standing up becomes a burden. Conclusions: Aim 1 illustrated that the reflex underlying IOH has a refractory period (<2 minutes) and a short sit blunts the IOH response. Aim 2 illustrated that both sympathetic activation and muscle activation plays an important role in mitigating the IOH BP response. Aim 3 concluded that both muscle pre-activation and post-tensing reduces the IOH BP drop and symptoms. Aim 4 illustrated that IOH negatively affects many aspects of patient life, including social, employment, and emotional aspects.