Ezetimibe (EZB) lowers cholesterol by blocking cholesterol absorption in the intestine. Data with EZB are limited in HIV-infected patients. We enrolled HIV-infected adults in this prospective, noncontrolled, single-center pilot study if their low-density lipoprotein (LDL) was not at goal despite therapy with a statin. Stable protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) and a low-dose statin were required for inclusion. The primary endpoint was LDL reduction at 18 weeks. In a subgroup of patients on lopinavir/ritonavir (LPV/r), trough concentrations were obtained before and after addition of EZB. Twenty patients were enrolled; 12 (60%) men, 18 (90%) African American. HAART included ritonavir (RTV)-boosted PIs in 17 (85%) patients; 3 (15%) were on nelfinavir. Mean percent changes from baseline in LDL were -10.9%, -12.2%, and -12.4% at weeks 6, 12, and 18, respectively (p < 0.05 for each time period vs. baseline). Mean percent changes from baseline in total cholesterol (TC) were -11.1%, -9.6%, and 9.1% at weeks 6, 12, and 18, respectively (p < 0.05 at each time period vs. baseline). No significant changes in triglycerides, high-density lipoprotein, and LPV/r concentrations were seen. One patient experienced elevated creatine phosphokinase possibly related to study medication; no other adverse effects were seen. Addition of EZB to low-dose statin effectively lowers LDL and TC and appears to be safe and well tolerated.