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Background and Study Aims: Positron emission tomography/computed tomography (PET/CT) with 2-[18F]FDG (FDG) has been increasingly used to detect or monitor neoplasms. Gastrointestinal tract (GIT) is one of the most common sites of FDG uptake, leading to increasing requests for endoscopic examinations. We aimed to evaluate the nature and significance of unexpected PET/CT-FDG findings in the GIT. Patients and Methods: We retrospectively analyzed 371 consecutive patients with incidental GIT findings on PET/CT-FDG between June 2016 and October 2021 who were subsequently referred to endoscopic examinations. Demographic data, PET/CT-FDG results, endoscopic findings, and histological analysis were analyzed. Results: Of 194 colonic incidental uptakes, 102 (52.6%) corresponded to at least premalignant lesions, being 57 (29.4%) advanced adenomas and 23 (11.9%) adenocarcinomas. Of 193 upper GIT incidental uptakes, there were 11 (13.8%) esophageal and 14 (14.4%) gastric malignant/premalignant lesions. The maximum standardized uptake value (SUVmax) significantly varied according to the nature of the lesion, being higher in malignant lesions (in the esophagus, stomach, and colon). However, an optimal SUVmax cutoff was only found for stomach (SUVmax 8.2; sensitivity of 79% and specificity of 76%). There was a significant association between the site of uptake and the nature of the lesion – left colon and gastric body uptake were associated with neoplastic origin whereas rectum and lower esophagus were associated with inflammatory or no endoscopic changes. Conclusions: Any incidental uptake in the lower GIT should be investigated provided that patients are suitable for further treatment. However, in the upper GIT the characteristics of uptake on 18F‐FDG‐PET/CT may allow to select those who need endoscopic examination.