Elevated pulse pressure (PP) is increasingly being recognized as a cardiovascular risk factor. To investigate whether PP is associated with endothelial function in subjects with no apparent heart disease we prospectively assessed brachial flow-mediated dilation (FMD) in 525 consecutive subjects with no apparent heart disease [323 (61%) men, mean age 52 ± 11I years, mean body mass index (BMI) 26 ± 4 kg/m²]. Following an overnight fast and discontinuation of all medications for ≥ 12 hours, the FMD and endothelium-independent, nitroglycerin-mediated vasodilation (NTG) were assessed using high-resolution linear array ultrasound. Univariate linear analysis revealed a significant inverse association between FMD and PP ( r = —0.65, p < 0.01), systolic blood pressure ( r = —0.52, p < 0.01) and age ( r = —0.21, p < 0.05). Multivariate analysis showed that PP was the strongest independent predictor of FMD. We therefore divided the study population into two groups: group A ( n = 290) ≤ the median PP, and group B ( n = 235) > the median PP of 50 mmHg. Male sex, hypertension, diabetes, BMI, heart rate, and the use of aspirin, long-acting nitrates, calcium channel blockers, angiotensin-converting enzyme inhibitors and beta blockers were significantly more common in Group B compared with Group A. FMD but not NTG was significantly greater in patients with PP ≤ the median PP, compared with > the median PP (14.9 ± 7.9% vs 10.8 ± 8.8%, p < 0.001 and 16.1 ± 9.6% vs 14.8 ± 8.4%, p = 0.38; respectively). Thus, PP is inversely associated with brachial FMD in middle-aged subjects with no apparent heart disease, suggesting a potential mechanism whereby elevated PP contributes to cardiovascular disease. Long-term follow-up is warranted to elucidate the incidence of coronary artery disease in both study groups.