Objective: The red cell distribution width (RDW) is a basic parameter of the routine complete blood count, although usually overlooked by clinicians as part of the patient evaluation. Higher RDW levels have been associated with increased cardiovascular (CV) risk in several populations as well as in patients with hypertension. Endothelial dysfunction indicates target organ damage in patients with arterial hypertension. The integrity of endothelial glycocalyx (EG), a component of the endothelium, plays a vital role in vascular permeability, inflammation and elasticity and finally to CV disease. Smoking exerts a deleterious effect in arterial endothelium as well as it leads to hypertension disease. We aimed to explore any existing correlation between RDW and EG in newly diagnosed and never treated hypertensive patients regarding smoking habit. Design and method: We performed 24 h ambulatory blood pressure measurement, arterial stiffness estimation by carotid-femoral pulse wave velocity (PWV) and complete blood count in our whole population (n = 190, mean age = 50+10 years, 113 males, 24-h average SBP/DBP = 135+11/85+9). Increased perfusion boundary region (PBR) of the sublingual arterial microvessels (ranged from 5–9 micrometers) using Sideview Darkfield imaging (Microscan, Glycocheck) was measured as a non-invasive accurate index of reduced EG thickness. Results: A weak correlation between RDW and PBR 5–9 (r = 0.14, p < 0.05) was found in the whole population. Then our population was divided in two groups regarding smoking habit, smokers (n = 60, mean age = 48+9, males, 24-h average SBP/DBP = 135+11/85+9) and non-smokers (n = 130, mean age = 51+10, males, 24-h average SBP/DBP = 134+12/84+2). Smokers were younger than non-smokers (46+10 years vs. 51+10 years, p = 0.03) while no other differences were found as for BMI, 24 h SBP/DBP, renal function, cholesterol levels, PWV, RDW and PBR 5–9. Finally, we found in the smokers group an association between RDW and PBR 5–9 (beta = 0.33, p = 0.01) which was independent from blood pressure and cholesterol levels. Conclusions: It seems that that increased RDW, an inexpensive, easily counted, widely available, and detected without complex and expensive technologies, might give us valuable information regarding endothelial dysfunction in smokers, naïve hypertensive patients.