Macrophages in atherosclerotic plaques are responsible for weakening of the fibrous cap and may finally cause plaque rupture, whereas smooth muscle cells (SMCs) contribute to the tensile strength of the fibrous cap and consequently to plaque stability. Selective removal of macrophages from plaques via drug-induced macrophage death may be a promising strategy to alter plaque composition favouring plaque stabilisation. Macrophages are part of the innate immunity, express Toll-like receptors (TLRs) to recognise pathogens and induce autophagy as an innate defence mechanism to eliminate intracellular pathogens. Because macrophages but not SMCs express TLR7 in human and mouse plaques, we questioned 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 characterised by an increased number of vesicular structures containing cytoplasmic debris. Moreover, there was an increased turnover of microtubule-associated protein 1 light chain 3 (LC3-I) from the cytoplasm to LC3-II in autophagosomes, as demonstrated by western blotting. Accordingly, imiquimod stimulated the formation of autophagosomes in macrophages, which is a hallmark of autophagy. 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 the stabilisation of atherosclerotic plaques.