Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT), a functional imaging method, is usually performed on the entire torso, and regions of unexpected suspicious focal hypermetabolism are not infrequently observed. Among the regions, colon, thyroid, and prostate were found to be the common organs in a recent umbrella review. Some studies reported that a high rate of malignancy was shown in incidentally identified focal hypermetabolic regions and suggested that further examinations should not be ignored. To investigate the malignancy rate of incidental focal FDG uptake, useful PET parameters and their cutoffs in discrimination between malignant and benign lesions. Retrospectively, the final reports of 16510 F-18 FDG PET/CT scans performed at our hospital between January 2016 and March 2022 were reviewed to identify incidentally observed FDG uptake in the colon/rectum, thyroid, and prostate. The scans of patients with current or prior malignancies at each corresponding location, without the final reports of histopathology or colonoscopy (for colon and rectum) for the corresponding hypermetabolic regions, or with diffuse (not focal) hypermetabolism were excluded. Finally, 88 regions of focal colorectal hypermetabolism in 85 patients (48 men and 37 women with mean age 67.0 ± 13.4 years and 63.4 ± 15.8 years, respectively), 48 focal thyroid uptakes in 48 patients (12 men and 36 women with mean age 62.2 ± 13.1 years and 60.8 ± 12.4 years, respectively), and 39 focal prostate uptakes in 39 patients (mean age 71.8 ± 7.5 years) were eligible for this study. For those unexpected focal hypermetabolic regions, rates of malignancy were calculated, PET parameters, such as standardized uptake value (SUV), capable of distinguishing between malignant and benign lesions were investigated, and the cutoffs of those PET parameters were determined by plotting receiver operating characteristic curves. In the colon and rectum, 29.5% (26/88) were malignant and 33.0% (29/88) were premalignant lesions. Both SUVmax and SUVpeak differentiated malignant/premalignant from benign lesions, however, no parameters could distinguish malignant from premalignant lesions. Higher area under the curve was shown with SUVmax (0.752, 95%CI: 0.649-0.856, P < 0.001) and the cutoff was 7.6. In the thyroid, 60.4% (29/48) were malignant. The majority were well-differentiated thyroid cancers (89.7%, 26/29). The results of BRAF mutation tests were available for 20 of the 26 well-differentiated thyroid cancers and all 20 had the mutation. Solely SUVmax differentiated malignant from benign lesions and the cutoff was 6.9. In the prostate, 56.4% (22/39) were malignant. Only SUVmax differentiated malignant from benign lesions and the cutoff was 3.8. Overall, among the 175 focal hypermetabolic regions, 60.6% (106/175) were proven to be malignant and premalignant (in colon and rectum) lesions. Approximately 60% of the incidentally observed focal F-18 FDG uptake in the colon/rectum, thyroid, and prostate were found to be malignant. Of the several PET parameters, SUVmax was superior to others in distinguishing between malignant/premalignant and benign lesions. Based on these findings, incidental focal hypermetabolism should not be ignored and lead physicians to conduct further investigations with greater confidence.