Background: Recent studies, mainly on animal models, have suggested that negatively charged glycosaminoglycans, macrophages, and lymph vessels in the skin interstitium may serve as extrarenal control of sodium balance and blood pressure. The aim of the study was to prove the hypothesis that skin interstitium has a role in the pathogenesis of hypertension in humans. Methods and Results: We have examined skin biopsies in 91 patients from the department of surgery who had elective surgery with abdominal skin incision: 43 were hypertensive, 14 had resistant hypertension, and 34 with normal blood pressure as control group (median patients’ age in these groups estimated accordingly 64 vs. 64 vs. 61.5; p>0.05). We have studied (1) the content of Na+, water, accumulation of macrophages (CD68), and density of lymphatic vessels (D2-40) and blood vessels (CD31) in the specimens of abdominal skin taken at the time of surgery and (2) plasma NT-proANP, vascular endothelial growth factor (VEGF)-C, and VEGF-D concentrations. The study groups differed in skin expression of CD68 (control vs. hypertension vs. resistant hypertension groups were accordingly: 3.33 vs. 4.00 vs. 8.33; p=0.005) and in serum concentration of VEGF-C (5792 vs. 4348 vs. 3974pg/mL; p=0.026). Differences among groups in plasma NT-proANP levels were close to statistical significance (p=0.056). Conclusions: Our results confirm that skin interstitium may be involved in the pathogenesis of essential hypertension in humans. Lower levels of VEGF-C in hypertensive groups suggest that impairment of lymphangiogenesis and protective function of the skin lymphatic system may play a role in the pathogenesis of hypertension.