Angiogenesis is required for invasive tumor growth and metastasis which is controlled mainly by vascular endothelial growth factors (VEGF). Novel strategies for cancer treatment target VEGF signaling. These agents are featured by adverse events including hypertension. New concepts suggest that besides the kidneys, the skin also plays a role in body sodium homeostasis and blood pressure regulation by a VEGF-C–dependent buffering mechanism. Here, we tested the hypothesis that changes in blood pressure correspond to tissue sodium accumulation during sunitinib treatment of metastatic renal cell carcinoma patients (https://clinicaltrials.gov/identifier: NCT04368546; Charité ethical approval EA1/044/15).Male patients (n=4) took sunitinib according to the standard treatment protocol, 50 mg once daily, taken for 4 weeks followed by a 2-weeks off treatment period. Measurements were performed at baseline (before sunitinib treatment), and over a complete on-off-on period. Tissue sodium content was measured using non-invasive 23Na-MRI; skin sodium was measured in a group (n=5) of age-matched healthy subjects, as well. Blood pressure was measured according to AHA guidelines. Blood withdrawal followed after ca. 45 minutes of sitting to measure VEGF-A, VEGF-C, endothelin-1, renin and aldosterone levels.Elevated systolic blood pressure under sunitinib treatment decreased to the baseline level in the off-treatment phase (130.5 mmHg vs 117.5 mmHg, respectively, p<0.05). Plasma endothelin-1 levels mirrored directly and VEGF-A levels inversely the blood pressure changes. Baseline skin sodium content was similar to the skin sodium level of healthy controls. Skin sodium content was elevated after the first on-treatment phase and stayed high in all the following measurements in comparison to control subjects. Patients had high baseline VEGF-C levels that decreased after the first treatment with sunitinib and stayed low independently of further treatment phase.In conclusion, sunitinib treatment suppresses VEGF-C levels permanently which is associated with sustained elevated skin sodium levels. Furthermore, we confirmed the association between plasma endothelin-1 levels and blood pressure changes during sunitinib treatment protocol.