Background　Anticoagulants　induce　atherosclerosis　regression　in　animal　models　but　exploiting　this　clinically　is　limited　by　bleeding　events.　Here　we　test　a　novel　thrombin　inhibitor,　PTL060,　comprising　hirulog　covalently　linked　to　a　synthetic　myristoyl　electrostatic　switch　to　tether　to　cell　membranes.　Methods　and　Results　ApoE-/-　mice　were　fed　chow　or　high-fat　diets,　before　transplantation　of　congenic　aortic　segments　or　injection　of　PTL060,　parental　hirulog,　control　saline,　or　labeled　CD11b　positive　cells.　Aortic　transplants　from　transgenic　mice　expressing　anticoagulants　on　endothelium　did　not　develop　atherosclerosis.　A　single　intravenous　injection　of　PTL060,　but　not　hirulog　inhibited　atheroma　development　by　＞50%　compared　with　controls　when　assessed　4 weeks　later.　Mice　had　prolonged　bleeding　times　for　only　one　seventh　of　the　time　that　PTL060　was　biologically　active.　Repeated　weekly　injections　of　PTL060　but　not　hirulog　caused　regression　of　atheroma.　We　dissected　2　contributory　mechanisms.　First,　the　majority　of　CCR2+　(C-C　chemokine　receptor　type　2+)　monocytes　recruited　into　plaques　expressed　CCR7　(C-C　chemokine　receptor　type　7),　ABCA1　(ATP-binding　cassette　transporter　-　1),　and　interleukin-10　in　PTL060　mice,　a　phenotype　seen　in　＜20%　of　CCR2+　recruits　in　controls.　Second,　after　several　doses,　there　was　a　significant　reduction　in　monocyte　recruits,　the　majority　of　which　were　CCR2-negative　with　a　similar　regression-associated　phenotype.　Regression　equivalent　to　that　induced　by　intravenous　PTL060　was　induced　by　adoptive　transfer　of　CD11b+　cells　pre-coated　with　PTL060.　Conclusions　Covalent　linkage　of　a　myristoyl　electrostatic　switch　onto　hirulog　in　PTL060　uncouples　the　pharmacodynamic　effects　on　hemostasis　and　atherosclerosis,　such　that　plaque　regression,　mediated　predominantly　via　effects　on　monocytes,　is　accompanied　by　only　transient　anticoagulation.