Objective To determine the diagnostic accuracy of WB-MRI and 18 F-FDG PET/CT in detecting infltration pattern, disease activity, and response to treatment in patients with multiple myeloma (MM). Materials and methods Fifty-six patients with confrmed MM were included in the present study for pre-treatment evaluation. Among these individuals, 22 patients were available for the post-treatment evaluation of response to therapy. All patients were imaged with both WB-MRI and 18 F-FDG PET/CT. All radiographic fndings of infltration pattern, disease activity, and response to therapy were compared. The diagnostic performance of both modalities was estimated using bone marrow aspirate and biopsy as the reference test. Results For detection of active myelomatous tissue at diagnosis, WB-MRI achieved higher sensitivity (94%) than 18 F-FDG PET/CT (75%) (p = 0.0039), whereas both modalities achieved the same specifcity (80%). For detection of residual myelomatous tissue after treatment, 18 F-FDG PET/CT achieved higher specifcity (86%) than WB-MRI (43%) (p = 0.0081), whereas both modalities achieved the same sensitivity (75%). Conclusion WB-MRI is more sensitive than 18 F-FDG PET/CT in the diagnosis of MM before treatment; however, 18 F-FDG PET/CT is more specifc than WB-MRI in detecting residual involvement in treated patients.