Abstract Background G Protein Coupled Receptors and regulators of G-protein signalling (RGS), play a pivotal role in the signalling processes associated with atherosclerosis [1]. RGS5 is highly expressed in aortic tissue [2]. Development of atherosclerotic plaque is a complex process that involves foam cells originating from macrophages (Mϕ) and/or vascular smooth muscle cells (VSMCs). Differentiation of Mϕ and VSMC into various intermediary cells of varying inflammatory potency affects atherosclerotic plaque composition and vulnerability [3]. We hypothesize that RGS5 is involved in signalling of foam cell transition and thus, plaque biology. Purpose To evaluate the role of RGS5 on atherosclerotic plaque complexity and shifts of foam cell origin. Methods ApoE-/-RGS5+/+ and ApoE-/-RGS5-/- mice were fed a high fat Western Diet for 14 weeks. Cryosections bearing aortic valve cusps were used for staining. Lesion size was quantified on hematoxylin and eosin staining. Plaque composition was assessed by CD68, CD45, Oil red O and collagen staining. Triple staining was performed for CD45, CD68 and aSMA. Double immunofluorescent staining for CD45 and pro- and anti-inflammatory markers was carried out. Co-Localisation was analysed by Zeiss Zen. Data were analysed using Mann-Whitney-U test. Results Lesion size was significantly reduced in RGS5-deficient mice in comparison to control (in mm2: 0.398±0.02 vs 0.191±0.09, p=0.0001, n=15). Relative areas positive for Oil Red O and collagen did not differ between genotypes. Area positive for leukocyte marker CD45 increased significantly by 30.8% (p<0.0001, n=15), whereas area positive for CD68 was reduced by 10.3% (p=0.0292, n=15) in RGS5-deficient mice. Absence of RGS5 decreased co-localization of Mϕ-derived foam cells by 23% (p=0.03734, n=4-5) while leading to an 5.8% increase in aSMA-derived foam cells compared to control. Area positive for pro-inflammatory M1 Mϕ marker CD86 and iNOS increased by 36.3% and 36.8% after RGS5 knock-out (p<0.0001, n=15). No difference in M2 Mϕ positive area was observed when RGS5 was lacking. Conclusion RGS5 promotes plaque formation. The number of Mϕ-derived foam cells is increased by RGS5, while it reduces inflammatory M1 Mϕ. Interestingly, there were no differences in numbers of M2 Mϕ, indicating RGS5 inhibits VSMCs transition to M1 Mϕ resulting in an overall decrease of CD68-positive foam cells. Further study is required to determine molecular signalling of RGS5 that modulates the phenotype of Mϕ- and VSMC-derived cells. RGS5 could be useful as therapeutic target to suppress undesirable plaque phenotypes and to reduce acute cardiovascular events.