The chemokine receptor CCR2 is known to be critically involved in atherosclerosis development, rendering blockade of the CCL2-CCR2 axis of therapeutic interest. CCR2 antagonists have, however, limited clinical success. Interestingly, it was shown for other drug targets that a measure for the dissociation of the drug-receptor complex, the so-called residence time (RT), can have a crucial impact on a drug’s efficacy. In this study, we thus aimed to determine whether an increased RT improves the therapeutic effectiveness of CCR2 antagonists. Carotid artery atherosclerosis was induced by collar placement in apoE -/- mice, followed by treatment with the short RT CCR2 antagonist 15b (RT=15 min, 150 μg/day), the long RT CCR2 antagonist 15a (RT=714 min, 150 μg/day) or vehicle control. After four weeks, atherosclerotic plaques were analyzed. Treatment with the CCR2 antagonists did not affect body weight or plasma cholesterol levels. At sacrifice, circulating CCR2 + monocyte numbers were only significantly reduced in the long RT 15a-treated mice (controls: 14.9±3.2*10 3 , 15b: 9.1±3.1*10 3 and 15a: 4.5±1.0*10 3 cells/mL, *P<0.05). Atherosclerotic plaque size was reduced from 64.4±11.8*10 3 μm 2 in control mice to 33.2±6.8*10 3 μm 2 in 15b-treated mice (-49%, *P<0.05), and even up to 17.6±4.1*10 3 μm 2 in 15a-treated mice (-73%, **P<0.01). Interestingly, relative plaque macrophage content was only decreased in 15a-treated mice compared to both control and 15b-treated mice (controls: 46±4%, 15b: 45±6%, 15a: 25±8%, *P<0.05), while neutrophil and mast cell numbers were not affected. In the aortic root, 15b did not significantly affect plaque size (controls: 252±25*10 3 μm 2 vs 15b: 196±17*10 3 μm 2 ), while the long RT CCR2 antagonist 15a inhibited plaque development to 157±15*10 3 μm 2 (-38%, **P<0.01). Also at that site of lesion development, macrophage area was only significantly reduced in the 15a-treated mice (controls: 35±4%, 15b: 32±3%, 15a: 23±4%, *P<0.05 compared to controls). In conclusion, our data demonstrate that the CCR2 antagonist with a long residence time was more effective in inhibiting atherosclerotic plaque development compared to the short RT antagonist, which implies that receptor residence time is an important parameter in drug development.