Context: HIV infection is associated with a greater risk for fasting hyperinsulinemia, impaired glucose tolerance, and higher incidence rates for vascular disease, myocardial infarction, or stroke despite effective combination antiretroviral therapy (cART). The underlying mechanism(s) may involve chronic low-grade systemic inflammation and immune cell activation. Dipeptidyl peptidase- 4 inhibitors (sitagliptin) improve glucose tolerance and may possess immunomodulatory effects because leukocyte CD26 cell surface receptors express dipeptidyl peptidase-4 activity. Objective: Sitagliptin will reduce inflammatory and immune cell activation markers known to be elevated in cART-treated HIV-infected (HIV+) adults with impaired glucose tolerance. Design: This was designed as a prospective, randomized, placebo-controlled, double-blind trial of sitagliptin in HIV+ adults. Setting: The setting was an academic medical center. Patients: Patients were cART-treated HIV+ men and women (n = 36) with stable HIV disease and impaired glucose tolerance. Interventions: Interventions included sitagliptin 100 mg/d or placebo for 8 weeks. Main Outcome Measures: At baseline and week 8, plasma high-sensitivity C-reactive protein and C-X-C motif chemokine 10 concentrations (ELISA), oral glucose tolerance,andabdominal sc adipose mRNAexpression forM1macrophage markers (monocyte chemotactic protein-1, EGF-like modulecontaining, mucin-like hormone receptor 1). Results: Sitagliptin reduced glucose area under the curve (P=.002) and improved oral glucose insulin sensitivity index (P=.04) more than placebo. Sitagliptin reduced plasma high-sensitivity C-reactive protein and C-X-C motif chemokine 10 levels more than placebo (P=.009). Adipose tissue monocyte chemotactic protein-1mRNAabundance declined significantly more (P<01), and adipose EGF-like module-containing, mucin-like hormone receptor 1 mRNA expression tended to decline more (P=.19) in sitagliptin than placebo. Conclusion: Sitagliptin had beneficial systemic and adipose anti-inflammatory effects in cARTtreated HIV+ adults with impaired glucose tolerance. Large-scale, long-term studies should determinewhethersitagliptin reduces cardiovascular riskandevents in HIV+adults.