To explore the utility of the 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT) in the differential diagnosis of IgG4-related lymphadenopathy (IgG4-RLAD) and angioimmunoblastic T-cell lymphoma (AITL).Retrospective analysis of 18F-FDG PET/CT imaging findings in clinically diagnosed IgG4-RLAD and AITL cases was undertaken to record the distribution, morphological characteristics, and imaging features of the affected lymph nodes, as well as FDG uptake of the spleen and bone marrow. Standardised uptake values normalised to lean body mass were evaluated for maximum (SULmax), average (SULavg), and peak values (SULpeak). Univariate and multivariate logistic regression was used to screen for statistically significant imaging findings to discriminate IgG4-RLAD from AITL.Twenty-two cases of IgG4-RLAD (17 men, five women, median age 49.5 years) and 22 cases of AITL (16 men, six women, median age 55 years) were finally included in the analysis. There were no AITL patients with involvement of a single lymph node region. AITL patients had more involvement of the different nodal regions except cervical and pelvic nodal regions. A practical assessment method based on a combination of SULpeak-LN/SULavg-liver, SULpeak-spleen, and the number of involved nodal regions, improved the performance for differential diagnosis between both groups with an overall classification accuracy of 90.9%.18F-FDG PET/CT is a useful tool for distinguishing AITL from IgG4-RLAD, and it can also help determine the optimal biopsy site for suspected cases of IgG4-RLAD or AITL, reduce the need for re-biopsy procedures, and enable physicians to develop timely treatment strategies.Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.