Background Dipeptidyl‐peptidase 4 ( DPP 4) inhibitors improve glycemic control in patients with diabetes mellitus by preventing the degradation of glucagon‐like peptide‐1 ( GLP ‐1). GLP ‐1 causes vasodilation in animal models but also increases sympathetic activity; the effect of GLP ‐1 in the human vasculature and how it is altered by DPP 4 inhibition is not known. DPP 4 also degrades the vasodilator brain natriuretic peptide ( BNP ) to a less potent metabolite. This study tested the hypothesis that DPP 4 inhibition potentiates the vasodilator responses to GLP ‐1 and BNP in the human forearm. Method and Results Seventeen healthy subjects participated in this randomized, double‐blinded, placebo‐controlled crossover study. On each study day, subjects received DPP 4 inhibitor (sitagliptin 200 mg by mouth) or placebo. Sitagliptin increased forearm blood flow and decreased forearm vascular resistance without affecting mean arterial pressure and pulse. GLP ‐1 and BNP were infused in incremental doses via brachial artery. Venous GLP ‐1 concentrations were significantly higher during sitagliptin use, yet there was no effect of GLP ‐1 on forearm blood flow in the presence or absence of sitagliptin. BNP caused dose‐dependent vasodilation; however, sitagliptin did not affect this response. GLP ‐1 and BNP had no effect on net norepinephrine release. Conclusions These data suggest that GLP ‐1 does not act as a direct vasodilator in humans and does not contribute to sympathetic activation. Sitagliptin does not regulate vascular function in healthy humans by affecting the degradation of GLP ‐1 and BNP . Clinical Trial Registration URL : www.clinicaltrials.gov/ Unique identifier: NCT 01413542.