Purpose: To investigate the performance of pretreatment fluorine 18 ( 18 F) fluorodeoxyglucose PET/CT radiomics in predicting severe immune-related adverse events (irSAEs) among patients with advanced non-small cell lung cancer (NSCLC) treated with immunotherapy, which is important in optimizing treatment plans and alleviating future complications with early interventions., Materials and Methods: The retrospective arm of this study included 146 patients with histologically confirmed stage IIIB-IV NSCLC who were treated with immune checkpoint blockade between June 2011 and December 2017 and who were split into training ( n = 97) and test ( n = 49) cohorts. A prospective validation arm enrolled 48 patients before initiation of immunotherapy between January 2018 and June 2019 as an independent test cohort. Radiomics features extracted from baseline (preimmunotherapy treatment) PET, CT, and PET/CT fusion images were used to generate a radiomics score (RS) to quantify patient risk for developing irSAEs by an improved least absolute shrinkage and selection operator method. Weighted multivariable logistic regression analysis was then used to develop a nomogram model to predict irSAEs, which was assessed by its calibration, discrimination, and clinical usefulness., Results: The radiomics nomogram, incorporating the RS, type of immune checkpoint blockade, and dosing schedule, was able to predict patients with and without irSAEs with area under the receiver operating characteristic curve of 0.92 (95% confidence interval [CI]: 0.86, 0.98), 0.92 (95% CI: 0.86, 0.99), and 0.88 (95% CI: 0.78, 0.97) in the training, test, and prospective validation cohorts, respectively. Decision curve analysis showed that the radiomics nomogram model had the highest overall net benefit., Conclusion: A high RS is a significant risk factor for development of irSAEs, demonstrating the value of PET/CT images in predicting irSAEs. By the identification, at baseline, of patients with NSCLC most likely to have irSAEs, treatment plans can be optimized before initiation of immunotherapy. Supplemental material is available for this article. © RSNA, 2020See also the commentary by Yousefi., Competing Interests: Disclosures of Conflicts of Interest: W.M. disclosed no relevant relationships. I.T. disclosed no relevant relationships. J.Q. disclosed no relevant relationships. M.B.S. disclosed no relevant relationships. R.J.G. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: board member for HealthMyne, grants from Helix BioPharma, stock in HealthMyne, Molecular Templates, and Helix BioPharma. Other relationships: patents 60/865,544 (Systems, Methods, and Devices for Analyzing Quantitative Information Obtained from Radiological Images) and 61/890,217 (Systems and Methods for Diagnosing Tumors in a Subject by Performing a Quantitative Analysis of Texture-based Features of a Tumor Object in a Radiological Image), pending patents 10MA024PR2 (Noninvasive Detection of Breast Cancer Lymph Node Metastasis using Carbonic Anhydrases IX and XII Targeted Imaging Probes) and 11MA026PR (Identification and Validation of Surrogate Markers for Colon Adenoma and Adenocarcinoma)., (2020 by the Radiological Society of North America, Inc.)