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Purpose Deriving links between imaging and genomic markers is an evolving field. 2-[18F]FDG PET/CT (18F-fluorodeoxyglucose positron emission tomography–computed tomography) is commonly used for cancer imaging, with maximum standardized uptake value (SUVmax) as the main quantitative parameter. Tumor mutational burden (TMB), the quantitative variable obtained using next-generation sequencing on a tissue biopsy sample, is a putative immunotherapy response predictor. We report the relationship between TMB and SUVmax, linking these two important parameters. Methods In this pilot study, we analyzed 1923 patients with diverse cancers and available TMB values. Overall, 273 patients met our eligibility criteria in that they had no systemic treatment prior to imaging/biopsy, and also had 2-[18F]FDG PET/CT within 6 months prior to the tissue biopsy, to ensure acceptable temporal correlation between imaging and genomic evaluation. Results We found a linear correlation between TMB and SUVmax (p max, whereas age, gender, and tumor organ did not. Conclusion Our observations link SUVmax in readily available, routinely used, and noninvasive 2-[18F]FDG PET/CT imaging to the TMB, which requires a tissue biopsy and time to process. Since higher TMB has been implicated as a prognostic biomarker for better outcomes after immunotherapy, further investigation will be needed to determine if SUVmax can stratify patient response to immunotherapy.