Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking bloodmonocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Becausemacrophage proliferation was recently shown to dominatemacrophage accumulation in advanced plaques, locally inhibitingmacrophage proliferationmay reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E-deficientmice (Apoe-/-)with advanced atherosclerotic plaques. This resulted in the rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an 8-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting localmacrophage proliferation can effectively treat inflammation in atherosclerosis.