UNLABELLED: The aim of this study was to compare the detection of bone metastases by 99mTc-methylene diphosphonate (99mTc-MDP) planar bone scintigraphy (BS), SPECT, 18F-Fluoride PET, and 18F-Fluoride PET/CT in patients with high-risk prostate cancer. METHODS: In a prospective study, BS and 18F-Fluoride PET/CT were performed on the same day in 44 patients with high-risk prostate cancer. In 20 of the latter patients planar BS was followed by single field-of-view (FOV) SPECT and in 24 patients by multi-FOV SPECT of the axial skeleton. Lesions were interpreted separately on each of the 4 modalities as normal, benign, equivocal, or malignant. RESULTS: In patient-based analysis, 23 patients had skeletal metastatic spread (52%) and 21 did not. Categorizing equivocal and malignant interpretation as suggestive for malignancy, the sensitivity, specificity, positive predictive value, and negative predictive value of planar BS were 70%, 57%, 64%, and 55%, respectively, of multi-FOV SPECT were 92%, 82%, 86%, and 90%, of (18)F-Fluoride PET were 100%, 62%, 74%, and 100%, and of 18F-Fluoride PET/CT were 100% for all parameters. Using the McNemar test, 18F-Fluoride PET/CT was statistically more sensitive and more specific than planar or SPECT BS (P < 0.05) and more specific than 18F-Fluoride PET (P < 0.001). SPECT was statistically more sensitive and more specific than planar BS (P < 0.05) but was less sensitive than 18F-Fluoride PET (P < 0.05). In lesion-based analysis, 156 lesions with increased uptake of 18F-Fluoride were assessed. Based on the corresponding appearance on CT, lesions were categorized by PET/CT as benign (n = 99), osteoblastic metastasis (n = 46), or equivocal when CT was normal (n = 11). Of the 156 18F-Fluoride lesions, 81 lesions (52%), including 34 metastases, were overlooked with normal appearance on planar BS. SPECT identified 62% of the lesions overlooked by planar BS. 18F-Fluoride PET/CT was more sensitive and more specific than BS (P < 0.001) and more specific than PET alone (P < 0.001). CONCLUSION: 18F-Fluoride PET/CT is a highly sensitive and specific modality for detection of bone metastases in patients with high-risk prostate cancer. It is more specific than 18F-Fluoride PET alone and more sensitive and specific than planar and SPECT BS. Detection of bone metastases is improved by SPECT compared with planar BS and by 18F-Fluoride PET compared with SPECT. This added value of 18F-Fluoride PET/CT may beneficially impact the clinical management of patients with high-risk prostate cancer.