Rupture-prone atherosclerotic plaques have a large necrotic core, numerous macrophages and a thin fibrous cap that consists of collagen-synthesizing smooth muscle cells (SMCs) and extracellular matrix. Plaques tend to rupture as a consequence of a weakened fibrous cap, particularly in the shoulder regions where most macrophages reside. Lesional macrophages produce matrix metalloproteinases that degrade the extracellular matrix, and induce SMC apoptosis which leads to a decrease in collagen-producing cells. Selective removal of macrophages from plaques by inducing macrophage-specific cell death may be a promising strategy to alter plaque composition, favoring plaque stability. Macrophages express Toll-like receptors (TLRs) to recognize pathogens, and eliminate intracellular pathogens by inducing autophagy. Since macrophages in human atherosclerotic plaques express TLR7, we investigated whether TLR7 ligands can selectively induce autophagy in macrophages. In vitro, the TLR7 ligand imiquimod induced cell death in a concentration-dependent manner in cultured macrophages but not in SMCs. Transmission electron microscopy (TEM) showed that imiquimod-induced cell death was characterized by an increased number of vesicular structures containing cytoplasmic debris, called autophagosomes, which is a hallmark of autophagy. The effects of imiquimod were abolished in TLR7-deficient macrophages, indicating that imiquimod induces autophagy via TLR7. Local in vivo administration of imiquimod to rabbit atherosclerotic carotid arteries reduced the macrophage content in the plaques through autophagy, as shown by TEM, whereas the amount of SMCs was unaffected. In conclusion, imiquimod selectively decreased the macrophage load in rabbit atherosclerotic plaques. Therefore, TLR7 appears to be a promising pharmacological target for stabilizing atherosclerotic plaques.