A 71-year-old man with newly diagnosed malignant mesothelioma was referred for an F-18 FDG PET/CT study to evaluate the extent of disease. PET showed mild FDG uptake in the right chest, corresponding to a lobulated, mass-like right pleural effusion versus thickening involving the entire right pleural space, and some mediastinal involvement, on the accompanying CT scan. In addition, marked FDG uptake was seen in the proximal left humerus, suspicious for an osseous metastasis. The corresponding CT scan findings of cortical thickening and a Swiss cheese appearance were most consistent with Paget disease. The intense FDG uptake in an osseous lesion on FDG-PET in our case reminds us of the variable nature of FDG uptake in Paget disease, the possibility of false-positive findings on FDG-PET in patients with cancer, and the usefulness of the fusion techniques in the evaluation of skeletal lesions, with the potential for discriminating between benign Paget disease and other pathologic bone findings.