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PET with 18 F-FDG is the standard modality in nuclear medicine for imaging multiple myeloma (MM). However, viable MM as detected by MRI or PET with other metabolic tracers, including 11 C-methionine, may be missed-for example, because of low hexokinase 2 (HK2) expression of tumor cells. The aim of this study was to further investigate potential reasons for PET false negativity. Methods: A cohort of 15 mainly pretreated patients with relapsed or refractory biopsy-proven, serologically active MM who underwent both 18 F-FDG and 11 C-methionine PET/CT was retrospectively analyzed. Results: In 9 of the 15 patients, 18 F-FDG PET was negative in the presence of viable disease. In the remaining 6 patients, both 18 F-FDG and 11 C-methionine PET/CT revealed the same number of MM lesions. At immunohistochemistry, 18 F-FDG-negative myeloma did not exhibit significant differences in HK2 or glucose-6-phosphatase expression from 18 F-FDG-positive disease ( P = 0.57 and P = 0.44, respectively). Conclusion: Beyond HK2 expression, 18 F-FDG negativity in (mainly pretreated) MM patients seems to be associated with additional causes not yet known., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)