The acantholytic variant of squamous carcinoma (ASC) represents a rare type of metaplastic breast carcinoma with typical occurrence of pseudoglandular and pseudovascular structures, arising as a result of cohesion loss between the neoplastic cells. Up to the present, there have been only 10 cases of mammary ASC described in the English written literature. The authors present a case of a 57-year-old woman with a large (6 x 7 cm) suspicious lump on ultrasonography in her right breast treated by mastectomy with an ipsilateral axillary lymph node dissection due to histologically verified ASC. Additional postoperative staging computer tomography revealed metastatic foci in the left lungs, thus calling for adjuvant chemotherapy for the patient. Six months after setting the diagnosis, the patient is alive with a partial therapeutic response. In the differential diagnosis of ASC it is important to exclude angiosarcoma, phyllodes tumor and metastatic sarcomas to the breast. The useful tools for differentiation between the above-mentioned entities are extensive bioptic examination and detailed immunohistochemical staining, enabling the pathologist to exclude the endothelial lineage (using CD31 and CD34) and to verify the epithelial origin through the detection of cytokeratins (spectra of high-molecular weight cytokeratins). Furthermore, the ASC shows positive immunohistochemical staining for markers of the myoepithelial differentiation, e.g. cytokeratin 14, CD10 and p63, suggesting an immature cell population with basaloid features. In conclusion, as ASC is an aggressive subtype of the breast carcinoma with a poor prognosis, the correct diagnosis set by the pathologist is of great importance on the therapeutic management in affected patients.