Introduction: The literature reports rare cases of isolated axillary lymph node metastasis from cancer of unknown primary (CUP). The authors reviewed the prevalence and outcome of patients with isolated axillary nodal swelling suspicious for malignancy affected or not by isolated axillary node metastasis from CUP. Materials and Methods: The authors collected data about 65 patients presented with isolated axillary lymph node swelling who underwent axillary lymph node excisional biopsy for malignancy suspicion, between January 2005 and December 2011, in the absence of any specific diagnosis. Results: Histological examination revealed a metastatic infiltration by an occult solid cancer in 16 cases (24%), ten of which were occult breast cancers. Histological patterns and molecular markers allowed in all cases of occult cancer a probable identification of the primary tumor site, while a definitive diagnosis was possible only in the 56.25% of cases (9/16). The prognosis of these patients was very poor with a five-year overall survival of 28%, and thus very similar to patients affected by Stage IV overt breast cancer. Conclusions: Among occult malignancies presenting with sole axillary lymph node metastasis, breast cancer remains the more probable primary cancer, but many other sites should be taken into consideration by negative breast imaging. Positron-emission tomography computed tomography (PET-CT) resulted helpful in the primary site detection, but has nonetheless a margin of failure. Occult breast cancers behave very similar to Stage IV overt breast cancers, and should be treated accordingly.