Objectives: To prospectively investigate determinants of the accuracy of staging axillary lymph nodes in breast cancer using [F-18]fluorodeoxyglucose positron emission tomography (FDG PET). Methods: Patients with primary operable breast cancer underwent FDG PET of the chest followed by sentinel node biopsy (SNB, n = 47) and/or complete axillary lymph node dissection (ALND, n = 23). PET scans were independently interpreted by three observers in a blinded fashion with respect to the FDG avidity of the primary tumor and the axillary status. The results were compared to histopathological analyses of the axillary lymph nodes. Clinicians were blinded to the PET results. Results: Axillary lymph node specimens and FDG PET scans were evaluated in 70 patients (59% cT1). Overall, 32 (46%) had lymph node metastases as established bv SNB (18/47) or ALND (14/23), 20 of which were confined to a single node. The overall sensitivity of FDG PET was 25%, with a specificity of 97%. PET results were false-negative in all 18 positive SNBs and true-positive in 8/14 in the ALND group. The performance of FDG PET depended on the axillary tumor load and the FDG avidity of the primary tumor. Intense uptake in the primary tumor was found in only 57% of the patients, and this was independent of the size. There was excellent interobserver agreement of visual assessment of FDG uptake in primary tumor and axillary lymph nodes. Conclusions: The sensitivity of FDG PET to detect occult axillary metastases in operable breast cancer was low, and it was a function of axillary tumor load and FDG avidity of the primary tumor. Even though the clinical relevance of occult disease detected by SNB needs to be confirmed, it is suggested that FDG PET in these patients should be focused on exploiting its nearly perfect specificity and the potential prognostic relevance of variable FDG uptake.