PurposeThis study is to develop a structured approach to distinguishing large-artery vasculitis from atherosclerosis using 18-fluorodeoxyglucose positron emission tomography combined with low-dose computed tomography (FDG PET/CT).MethodsFDG PET/CT images of 60 patients were evaluated, 30 having biopsy-proven giant cell arteritis (GCA; the most common form of large-artery vasculitis), and 30 with severe atherosclerosis. Images were evaluated by 12 nuclear medicine physicians using 5 criteria: FDG uptake pattern (intensity, distribution, circularity), the degree of calcification, and co-localization of calcifications with FDG-uptake. Criteria that passed agreement, and reliability tests were subsequently analysed for accuracy using receiver operator curve (ROC) analyses. Criteria that showed discriminative ability were then combined in a multi-component scoring system. Both initial and final ‘gestalt’ conclusion were also reported by observers before and after detailed examination of the images.ResultsAgreement and reliability analyses disqualified 3 of the 5 criteria, leaving only FDG uptake intensity compared to liver uptake and arterial wall calcification for potential use in a scoring system. ROC analysis showed an area under the curve (AUC) of 0.90 (95%CI 0.87–0.92) for FDG uptake intensity. Degree of calcification showed poor discriminative ability on its own (AUC of 0.62; 95%CI 0.58–0.66). When combining presence of calcification with FDG uptake intensity into a 6-tiered scoring system, the AUC remained similar at 0.91 (95%CI 0.88–0.93). After exclusion of cases with arterial prostheses, the AUC increased to 0.93 (95%CI 0.91–0.95). The accuracy of the ‘gestalt’ conclusion was initially 89% (95%CI 86–91%) and increased to 93% (95%CI 91–95%) after detailed image examination.ConclusionStandardised assessment of arterial wall FDG uptake intensity, preferably combined with assessment of arterial calcifications into a scoring method, enables accurate, but not perfect, distinction between large artery vasculitis and atherosclerosis.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00259-023-06220-5.