Background and aims: The objective of this study was to investigate the effects of semaglutide, a long acting glucagon-like peptide-1 receptor agonist, on atherosclerotic inflammation and calcification using a multimodality positron emission tomography and computed tomography (PET/CT) approach. Methods: Atherosclerotic New Zealand White rabbits were randomized to an intervention- (n = 12) or placebo group (n = 11) receiving either semaglutide or saline-placebo. PET/CT imaging was done before and after 16-weeks of intervention. Three different radiotracers were used: [⁶⁴Cu]Cu-DOTATATE for imaging of activated macrophages, [¹⁸F]FDG imaging cellular metabolism and [¹⁸F]NaF PET visualizing micro-calcifications. Tracer uptake was quantified by maximum standardized uptake value (SUV_max) and target-to-background-ratio (TBR_max). Animals were euthanized for autoradiographic imaging and histological analyses. Results: A reduction in activated macrophage tracer-uptake was observed in the semaglutide group (SUV_max: p = 0.001 and TBR_max: p = 0.029). When imaging cellular metabolism, an attenuation of SUV_max and TBR_max was observed in the semaglutide group (p = 0.034 and p = 0.044). We found no difference in uptake of the micro-calcification tracer between the two groups (SUV_max: p = 0.62 and TBR_max: p = 0.36). Values of macrophage density in the vessel wall were significantly correlated with SUV_max values of the activated macrophage (r = 0.54, p = 0.0086) and cellular metabolism tracers (r = 0.51, p = 0.013). Conclusions: Semaglutide decreased vascular uptake of tracers imaging activated macrophages and cellular metabolism but not micro-calcifications compared to a saline placebo. This supports the hypothesis that semaglutide reduces atherosclerotic inflammation by means of decreased activated macrophage activity.