Apart from reducing plasma lipids, ezetimibe may produce non-lipid-related pleiotropic effects. The aim of this article was to compare the effect of ezetimibe and simvastatin on monocyte cytokine release and systemic inflammation in isolated hypercholesterolemic patients. One hundred thirty-four subjects with isolated hypercholesterolemia were allocated to 1 of 4 treatment groups treated for 90 days with, respectively, ezetimibe, simvastatin, ezetimibe plus simvastatin, or placebo. Monocyte cytokine release was determined at baseline and after 30 and 90 days of treatment. Compared with placebo, all the remaining treatment options reduced-monocyte release of tumor necrosis factor-α, interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1, which was accompanied by a reduction in plasma C-reactive protein levels. In subjects receiving both simvastatin and ezetimibe, posttreatment monocyte cytokine release and plasma C-reactive protein levels did not differ from those observed in 30 matched healthy subjects. Monocyte-suppressing and systemic-anti-inflammatory effects were more expressed in simvastatin- than in ezetimibe-treated patients and strongest when both the agents were administered together. The results obtained suggest that simvastatin may be a better treatment option than ezetimibe in isolated hypercholesterolemic patients and that hypercholesterolemic patients of high cardiovascular risk may benefit the most from combined treatment with simvastatin and ezetimibe.