Purpose: RGD peptide agents are potential candidates for vulnerable atherosclerotic plaque imaging that is ideal for direct risk stratification of fatal events. Recently a new radiolabeled RGD agent of ⁶⁸Ga-NOTA-RGD was developed. In this study, the feasibility and imaging characteristics of the ⁶⁸Ga-NOTA-RGD for atherosclerosis imaging was investigated in animal models and human studies. Methods: For an atherosclerosis animal model, ApoE^-/- mice were fed with high-fat western diet for more than 20 weeks. To evaluate the feasibility of ⁶⁸Ga-NOTA-RGD for atherosclerosis imaging, tissue uptakes of ⁶⁸Ga-NOTA-RGD in the major organs of heart, liver, and lungs were measured in ApoE^-/- and control mice, and compared with those of ¹⁸F-FDG. In vivo ⁶⁸Ga-NOTA-RGD and ¹⁸F-FDG positron emission tomography (PET) imaging was also performed in ApoE^-/- and control mice, after determination of imaging protocol from dynamic PET scans. Uptakes in the thoracic aorta were compared between ApoE^-/- and control mice, and the same analysis was also performed for ¹⁸F-FDG PET. In human PET scans, the kinetic characteristics and feasibility of ⁶⁸Ga-NOTA-RGD PET were assessed in 4 patients with known coronary artery disease. On dynamic PET images, graphical analysis adopting Logan plotting was tested for model appropriateness, by measuring distribution volumes and binding potentials of the liver and muscle. On static PET images, aorta-to-jugular-ratios were measured and compared with clinical findings. Results: In tissue uptake study, uptake of both ⁶⁸Ga-RGD and ¹⁸F-FDG in the thoracic aorta was higher in ApoE^-/- than control mice. On PET scans, the relative uptake values of the thoracic aorta was significantly higher in ApoE^-/- than in control mice with both of ⁶⁸Ga-RGD (P = 0.024) and ¹⁸F-FDG (P = 0.038). However, the uptake was more definite with ¹⁸F-FDG PET. In human PET studies, appropriateness of the application of reversible binding model and Logan plotting was demonstrated. The aorta-to-jugular ratios were measured up to 1.25 in mild atherosclerotic patients, and demonstrated tendency of correlation with serum high-sensitivity C-reactive protein. Conclusions: ⁶⁸Ga-NOTA-RGD has a potential for an in vivo atherosclerosis imaging agents. However, the imaging contrast and sensitivity of ⁶⁸Ga-NOTA-RGD PET was lower than that of ¹⁸F-FDG PET, which may be a limitation for clinical application.