Multiple myeloma (MM) is a disease characterized by a monoclonal plasma cell population in the bone marrow whereby osseous involvement is a predominant feature. The aim of this prospective study was to investigate the combined use of F-18 FDG and F-18 NaF PET/CT in the skeletal assessment of patients with MM and to compare the efficacy of these two PET tracers regarding detection of myeloma-indicative osseous lesions. A total of 26 patients (14 females and 12 males, mean age 61.8 ± 1.8 years (range 40–81 years)) with MM diagnosed according to standard criteria. All patients underwent both F-18 FDG PET/CT and F-18 NaF PET/CT scans within 1 week after the completion of the usual staging workup for MM. In total, approximately 128 focal F-18 FDG avid skeletal lesions were detected; the stage I (n = 5) patients had 10 bone lesions, the stage II (n = 11) patients had 43 lesions, and the stage III (n = 10) patients demonstrated 75 focal bone lesions. F-18 NaF PET/CTs demonstrated fewer myeloma indicative lesions than F-18 FDG PET/CTs. Totally, 57 focal bone lesions were detected with whole body F-18 NaF PET/CT (mean 2.19 ± 0.34, between 1 and 9 lesions); the five stage I patients had 6 bone lesions, the 11 stage II pts had 18 lesions, and the ten stage III patients demonstrated 33 focal bone lesions. On the other hand, F-18 NaF PET/CT demonstrated additional 135 bone lesions defined as rib fractures and other findings due to degenerative changes. In conclusion, our study implies that F-18 NaF PET/CT scan did not actually aid for assessing the myelomatous bone lesions in patients with MM. Therefore, a complementary F-18 NaF PET/CT may be an accurate modality for detecting of bone fracture in patients with MM.