The primary tumor of brain metastases (BM) is unknown in up to one-half of BM at the time of neurosurgery. Fifty-four consecutive unselected BM were investigated immunohistochemically using antibodies against different intermediate filaments and tumor markers. By correlating the immunohistochemical results with the location of the primary tumor, a staining pattern characteristic of the most frequent BM could be established. Subsequently, 40 cases with known primary tumor were blinded and re-evaluated based on their immunohistochemical staining pattern. Lung (20.4%), colorectum (11.1%), melanoma (7.4%), and breast (7.4%) were the most common primaries. In 14 (25.9%) cases, the primary was unknown. The characteristic immunohistochemical profiles of BM were found to be positivity of cytokeratin 7 and thyroid transcription factor-1 (TTF-1) pointing to the lung, positivity of cytokeratin 20 and negativity of cytokeratin 7 pointing to the colorectum, positivity of vimentin and protein S100 and negativity of cytokeratins (CK) pointing to a melanoma, and positivity of cytokeratin 7 and CA 15-3 with negativity of TTF-1, CA 125 and CA 19-9 pointing to the breast. These primaries comprise the majority in our series. Using the established panel of immunohistochemical markers, we were able to identify the primary in 29 out of 40 (72.5%) BM correctly. To predict the primaries of BM, a combination of antibodies against different CK, vimentin, protein S100, TTF-1, and CA 15-3 is able to point to the primary site in BM of the unknown primary.