PURPOSE: The aim of the study was to prospectively compare the diagnostic value of whole-body diffusion-weighted imaging (DWI) and FDG PET/CT for breast cancer (BC) staging. METHODS: Twenty BC patients underwent whole-body FDG PET/CT and 1.5-T DWI. Lesions with qualitatively elevated signal intensity on DW images (b = 800 s/mm(2)) were rated as suspicious for tumour and mapped to individual lesions and different compartments (overall 552 lesions). The apparent diffusion coefficient (ADC) value was determined for quantitative evaluation. Histopathology, MRI findings, bone scan findings, concordant findings between FDG PET/CT and DWI, CT follow-up scans and plausibility served as the standards of reference defining malignancy. RESULTS: According to the standards of reference, breasts harboured malignancy in 11, regional lymph nodes in 4, M1 lymph nodes in 3, bone in 7, lung in 2, liver in 3 and other tissues in 3 patients. On a compartment basis, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) for the detection of malignancies were 94, 99, 98, 97 and 98% for FDG PET/CT and 91, 72, 76, 50 and 96% for DWI, respectively. Of the lesions seen on DWI only, 348 (82%) turned out to be false-positive compared to 23 (11%) on FDG PET/CT. The average lesion ADC was 820 +/- 300 with true-positive lesions having 929 +/- 252 vs 713 +/- 305 in false-positive lesions (p < 0.0001). CONCLUSION: Based on these initial data DWI seems to be a sensitive but unspecific modality for the detection of locoregional or metastatic BC disease. There was no possibility to quantitatively distinguish lesions using ADC. DWI alone may not be recommended as a whole-body staging alternative to FDG PET(/CT). Further studies are necessary addressing the question of whether full-body MRI including DWI may become an alternative to FDG PET/CT for whole-body breast cancer staging.