C-X-C motif chemokine receptor 4 (CXCR4) is expressed on the surface of various cell types involved in atherosclerosis, with a particularly rich receptor expression on macrophages and T cells. First pilot studies with 68Ga-Pentixafor, a novel CXCR4-directed positron emission tomography (PET) tracer, have shown promise to non-invasively image inflammation within atherosclerotic plaques. The aim of this retrospective study was to investigate the performance of 68Ga-Pentixafor PET/computed tomography (CT) for imaging atherosclerosis in comparison to 18F-FDG PET/CT. Methods: Ninety-two patients (37 females and 55 males; mean age 62 ± 10 years) underwent 68Ga-Pentixafor and 18F-FDG PET/CT for staging of oncologic diseases. In these subjects, arterial wall lesions in the large arteries were identified using morphological and PET-criteria of atherosclerosis (n = 652). Tracer uptake was measured and adjusted for vascular lumen (background) signal by calculation of target-to-background ratios (TBR) by two investigators blinded to the other PET scan. On a lesion-to-lesion and patient basis, TBR of both PET tracers were compared and additionally correlated to the degree of arterial calcification as quantified in CT. Results: On a lesion-to-lesion basis, 68Ga-Pentixafor and 18F-FDG uptake showed a weak correlation (TBR; r = 0.28; P < 0.01). 68Ga-Pentixafor PET identified more lesions (n = 290; TBR ≥ 1.6, P < 0.01) and demonstrated higher uptake than 18F-FDG PET (1.8 ± 0.5 vs. 1.4 ± 0.4; P < 0.01). The degree of plaque calcification correlated negatively with both 68Ga-Pentixafor and 18F-FDG uptake (r = -0.38 vs. r = -0.31, both P < 0.00001). Conclusion: CXCR4-directed imaging of the arterial wall with 68Ga-Pentixafor PET/CT identified more lesions as compared to 18F-FDG PET/CT, with only weak correlation between tracers. Further studies to elucidate the underlying biological mechanisms and sources of CXCR4 positivity, and to investigate the clinical utility of chemokine receptor-directed imaging of atherosclerosis are highly warranted. Copyright © 2019 by the Society of Nuclear Medicine and Molecular Imaging, Inc.