OBJECTIVE This study evaluated the semiquantitative and qualitative appearance of pigmented villonodular synovitis (PVNS) and giant cell tumor of the tendon sheath (GCTTS) on 18F-FDG PET/CT. METHODS An institutional review board-approved retrospective review was performed for patients diagnosed with GCTTS, focal PVNS, or diffuse PVNS who underwent PET/CT from 2003 to 2013. SUVmax and SUVmax/SUVmean of the liver (SUVr) were determined for each lesion on all available PET/CTs. Relevant conventional imaging and patient records were reviewed. RESULTS Fourteen patients (mean [SD] age, 52.8 [14.0] years; range, 26-74 years) were identified, 6 with 2 or more PET/CT examinations. The mean (SD) SUVmax and SUVr of all lesions were 8.7 (3.4; range, 4.0-14.5) and 3.9 (1.7; range, 2.0-7.1), respectively. There was no difference of the mean (SD) SUVmax (P = 0.10) or SUVr (P = 0.11) between focal PVNS (6.8 [3.0], 3.3 [1.9]), GCTTS (9.1 [3.0], 4.0 [1.2]), or diffuse PVNS (14.5, 7.1) subtypes. Of 29 comparison PET/CTs in 6 patients, 17 were performed after nontargeted chemotherapy and 12 without antecedent therapy. Significant SUVr fluctuations (>25%) occurred in 11 cases; no correlation existed between SUVr change and presence or absence of chemotherapy. CONCLUSIONS Pigmented villonodular synovitis and GCTTS can be intensely hypermetabolic, mimicking musculoskeletal metastases on 18F-FDG PET/CT. They may have significant SUV fluctuations, both during nontargeted chemotherapy and between treatments. The diagnosis of PVNS/GCTTS should be considered for focal intra-articular or juxta-articular FDG-avid lesions, and MRI is useful in further evaluation given the often diagnostic imaging features with this modality.