Aims: To assess the endothelial function of the skin microcirculation in chronic renal failure (CRF) independent of hypertension, we investigated the changes of the cutaneous blood flow induced by iontophoretic delivery of acetylcholine (ACh) and of sodium nitroprusside (SNP) in CRF patients free from arterial hypertension and in patients with essential hypertension. Methods: The study included 20 patients affected by CRF (mean creatinine clearance 12 ± 2 ml/min) without arterial hypertension (mean blood pressure 96 ± 1 mm Hg), 15 patients affected by essential hypertension (mean blood pressure 124 ± 1 mm Hg), and 20 normal controls. The changes of skin blood flow following iontophoretic delivery of ACh and of SNP were measured by laser Doppler flowmetry. Results: Following maximal ACh or SNP delivery, the change of blood flow from the baseline was similar both in normals (683 ± 92 vs. 684 ± 87%) and in CRF patients (778 ± 108 vs. 803 ± 124%), whereas in the hypertensives the response to ACh was lower than to SNP (434 ± 48 vs. 702 ± 98%, p < 0.01). Since the third ACh delivery dose, the skin blood flow increments were significantly lower in the hypertensive than in the CRF or in the normal control groups, whereas no difference was observed between uremics and controls. Conclusions: The endothelium-dependent hyperemia following ACh iontophoretic delivery is impaired in the skin microcirculation of essential hypertensive patients, but this is not the case in CRF patients with no history of arterial hypertension. This suggests that CRF per se, independent of arterial hypertension, is not associated with endothelial dysfunction of skin microcirculation.