Nitric oxide (NO) is an integral molecule especially important in the regulation of the cardiovascular system. Literature indicates that the number of studies continues to grow with regard to the effects of NO on cardiovascular disease and hypertension. “Prehypertension” is the clinical stage leading to hypertension. Diet and lifestyle modifications are the only treatment options for prehypertension. The objective of this study was to determine the effects of oral NO supplementation on blood pressure in patients with clinical prehypertension. This pilot phase study evaluated the effect of an orally disintegrating lozenge that generates NO in the oral cavity on blood pressure, functional capacity, and quality of life. Thirty patients with clinical prehypertension were recruited and enrolled in either the NO treatment or the placebo group over a 30-day period in an outpatient setting. Nitric oxide supplementation resulted in a significant decrease in resting blood pressure (138 ± 12 mm Hg in systole and 84 ± 5 mm Hg in diastole at baseline vs 126 ± 12 mm Hg in systole and 78 ± 4 mm Hg in diastole at follow-up, P < .001, vs baseline) and a significant increase in the achieved walking distance in the standard 6-minute walk test (596 ± 214 meters at baseline vs 650 ± 197 meters at follow-up, P < .005 vs baseline). Using a standardized questionnaire to assess quality of life, patients receiving NO supplementation showed improvement in the Physical Component Summary Score (PCS) and Mental Component Summary Score (MCS). Nitric oxide supplementation appears to lower blood pressure in patients with prehypertension and might be beneficial as a routine supplementation for cardiovascular protection.