Simple SummaryDifferent stimuli can influence posture in daily life and, therefore, impose a risk of a solid balance during standing. To maintain this upright position, the capacity to recognize changes in posture and react appropriately is essential. The increased frequency of falls owing to postural hypotension, along with a lack of postural stability, is a serious problem not just in the elderly, but also different patient groups (e.g., cardiac patients, diabetic patients, or patients recovering from stroke). Similar changes in blood pressure regulation, as well as cardio-postural control, might occur in patients suffering from lymphedema due to differences in fluid volumes of the lower limbs. Lymphedema therapy could therefore affect hemodynamic responses during orthostatic loading (sit-to-stand test) due to the variable amounts of fluid in the lower limbs throughout therapy. To our knowledge, no previous study has ever longitudinally investigated the inter-relationship between lymphedema and hemodynamic responses and changes in volume regulatory hormones during orthostatic loading over three weeks of lymphedema treatment. We report here that lymphedema patients did not show signs of orthostatic hypotension, demonstrating that those patients do not seem to be at an increased risk for orthostatic intolerance and falls. However, lymphedema treatment showed to have a potential beneficial effect on cardiovascular responses during orthostatic challenge (sit-to-stand test) in lymphedema patients.Background: Lymphedema arises due to a malfunction of the lymphatic system, leading to extensive tissue swelling. Complete decongestive therapy (CDT), which is a physical therapy lasting for 3 weeks and includes manual lymphatic drainages (MLD), leads to fluid mobilization and increases in plasma volume. Here, we investigated hemodynamic responses induced by these fluid shifts due to CDT and MLD. Methods: Hemodynamic parameters were assessed continuously during a sit-to-stand test (5 min baseline, 5 min of standing, and 5 min of recovery). This intervention was repeated on days 1, 2, 7, 14, and 21 of CDT, before and after MLD. Volume regulatory hormones were assessed in plasma samples. Results: A total number of 13 patients took part in this investigation. Resting diastolic blood pressure significantly decreased over three weeks of CDT (p = 0.048). No changes in baseline values were shown due to MLD. However, MLD led to a significant decrease in heart rate during orthostatic loading over all epochs on therapy day 14, as well as day 21. Volume regulatory hormones did not show changes over lymphedema therapy. Conclusion: We did not observe any signs of orthostatic hypotension at rest, as well as during to CDT, indicating that lymphedema patients do not display an elevated risk of orthostatic intolerance. Although baseline hemodynamics were not affected, MLD has shown to have potential beneficial effects on hemodynamic responses to a sit-to-stand test in patients undergoing lymphedema therapy.