Purpose The extent and intensity of $^{18}F$-FDG uptake in prostate cancer patients are known to be variable, and the clinical significance of focal $^{18}F$-fluorodeoxyglucose (1$^{18}F$-FDG) uptake that is incidentally found on positron emission tomography (PET) has not been established. We investigated the clinical significance of incidental focal prostate uptake of $^{18}F$-FDG on PET/computed tomography (CT) and analyzed differential findings on PET/CT between malignant and benign uptake. Methods A total of 14,854 whole-body $^{18}F$-FDG PET/CT scans (4,806 that were conducted during cancer screening and 10,048 that were conducted to evaluate suspected or alleged cancer outside of the prostate) were retrospectively reviewed to determine the presence, location, multiplicity and maximum standardized uptake value (SUVmax) of focal prostate uptake and combined calcification. The final diagnosis determined by serum prostate-specific antigen (PSA) level and biopsy was compared with PET findings. Results Incidental focal prostate uptake was observed in 148 of 14,854 scans (1.0 %). Sixty-seven of these 148 subjects who had diagnostic confirmation were selected for further analysis. Prostate cancer was diagnosed in nine of 67 subjects (13.4%). The remaining 58 subjects had no malignancy in the prostate based on normal serum PSA level (n=53), or elevated serum PSA level with a negative biopsy result (n=5). While 84.6% (11/13) of malignant uptake was peripherally located in the prostate glands, 60.2% (50/83) of benign uptake was centrally located (p<0.05). The positive predictive value of peripheral focal uptake for malignancy was 25%. The SUVmax, multiplicity and combined calcification were not significantly different between the two groups. Conclusion Although incidental focal $^{18}F$-FDG uptake in the prostate is not common, the incidence of cancer with focal uptake is not low. Therefore, these findings deserve further evaluation.The location of the focal prostate uptake may help with the selection of high-risk prostate cancer patients.