Background and Purpose— Adiponectin, the most abundantly secreted anti-inflammatory adipokine, protects against all stages of atherosclerotic plaque formation by acting on its receptors, AdipoR1 (adiponectin receptor 1) and AdipoR2 (adiponectin receptor 2). Through binding of AdipoR1, adiponectin leads to the activation of the AMPK (adenosine monophosphate–activated protein kinase) pathway, whereas stimulation of PPAR-α (peroxisome proliferator–activated receptor-α) is attributed to the binding of AdipoR2. However, the role of adiponectin and its receptors in plaque instability remains to be characterized. Thus, we aimed to investigate whether the adiponectin–AdipoR pathway is associated with carotid atherosclerotic plaque instability. Methods— The instability of plaque specimens obtained from patients who underwent a carotid endarterectomy (n=143) was assessed using gold standard histological classifications. Results— Using immunohistochemistry, we showed that adiponectin and AdipoR1/AdipoR2 are expressed in human carotid plaques and that their expression was localized most abundantly in areas of macrophage and foam cell accumulation. Unstable plaques expressed more adiponectin protein (Western blot, P <0.05) and less AdipoR2 mRNA (2.11-fold decrease, P <0.05) than stable plaques, whereas AdipoR1 expression remained similar between stable and unstable plaques. Beyond AdipoR1/AdipoR2 expression, a graded decrease in PPAR-α protein levels was observed in relation to carotid plaque instability ( P <0.001), whereas AMPK phosphorylation was increased ( P <0.05). Our in vitro model of plaque instability, involving the induction of foam cells from human THP-1 (Tamm–Horsfall protein 1) macrophages treated with acetylated low-density lipoprotein, supported our in vivo conclusions. Conclusions— An overall abundance of adiponectin with a decrease in AdipoR2 expression and activity was observed in unstable plaques, suggesting that reduced signaling through the AdipoR2 pathway, and not through AdipoR1, may contribute to plaque instability.