The effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on ambulatory blood pressure was assessed in nondiabetic patients with mild to moderate hypertension in a randomized, double-blind, placebo-controlled, 3-period crossover study. Nineteen patients on stable treatment with antihypertensive agent(s) received sitagliptin 100 mg b.i.d., 50 mg b.i.d., or placebo for 5 days, with at least a 7-day washout interval between periods. Twenty-four-hour ambulatory blood pressure, including systolic blood pressure, diastolic blood pressure, and mean arterial pressure, were monitored on days 1 and 5. Relative to placebo on day 1, the mean difference in 24-hour systolic blood pressure was -0.9 mm Hg (90% confidence interval: -2.9 to 1.1; P = .46) with sitagliptin 50 mg b.i.d. and -2.8 mm Hg (90% confidence interval: -4.9 to -0.8; P < .05) with 100 mg b.i.d. On day 5, the mean difference in 24-hour systolic blood pressure was -2.0 mm Hg (90% confidence interval: -3.5 to -0.4; P < .05) with 50 mg b.i.d. and -2.2 mm Hg (90% confidence interval: -3.7 to -0.6; P < .05) with 100 mg b.i.d. relative to placebo. For 24-hour diastolic blood pressure, there were no between-group differences in mean 24-hour diastolic blood pressure on day 1. On day 5, sitagliptin 50 mg and 100 mg b.i.d significantly (P < .05) lowered mean 24-hour diastolic blood pressure by -1.8 mm Hg (90% confidence interval: -2.8 to -0.8) and -1.6 mm Hg (90% confidence interval: -2.6 to -0.7), respectively, relative to placebo. Sitagliptin produced small but statistically significant reductions of 2 mm Hg to 3 mm Hg in 24-hour ambulatory blood pressure measurements acutely (day 1) and at steady state (day 5), and was generally well tolerated in nondiabetic patients with mild to moderate hypertension.