To evaluate the clinical significance of incidental focal prostate fluorodeoxyglucose (FDG) uptake, we reviewed 18-F-FDG positron emission tomography (PET)/CT scans from 2003 to 2007 and selected cases with focal FDG uptake in prostate. Cases of known prostate cancer were excluded. The maximum standardised uptake value (SUV(max)), site (central or peripheral) and pattern (discrete or ill-defined) of FDG uptake, calcification (present or absent) and prostate volume (<30 or ≥30 cc) were recorded. The PET/CT findings were correlated with serum prostate-specific antigen (PSA) levels, imaging studies, clinical follow-up and biopsy. Of a total of 5119 cases, 63 (1.2%) demonstrated focal FDG uptake in prostate. Eight cases were lost to follow-up. Among the 55 cases with follow-up, malignancy was confirmed by biopsy in 3 (5.4%). The three malignant cases had SUV(max) values of 3.3, 3.6 and 2.3, and all were noted in the peripheral portion of prostate; two of these cases had a discrete FDG uptake pattern, none had calcification corresponding to the FDG uptake area and one had a prostatic volume greater than 30 cc. The mean SUV(max) of 52 benign cases was 3.2 ± 1.7 and focal FDG uptake was noted in the peripheral portion in 34 (65%), 20 (38%) cases showed a discrete FDG uptake pattern, 35 (67%) were accompanied by calcification and 32 (62%) had a prostatic volume greater than 30 cc. The majority of cases demonstrating focal FDG uptake in prostate were benign and no PET/CT finding could reliably differentiate benign from malignant lesions; however, when discrete focal FDG uptake without coincidental calcification is seen, particularly in the peripheral zone of the prostate, further clinical evaluation is recommended.