The diagnosis of metastatic adenocarcinoma to the brain of unknown primary is problematic, and the role of immunohistochemistry in identifying a source has not been fully characterized. Sixty-eight metastatic adenocarcinomas of the brain with known primaries were immunostained with antibodies to cytokeratin 7 (CK7), cytokeratin 20 (CK20), CAM 5.2, wide-spectrum keratin (WSK), gross cystic disease fluid protein-15 (GCDFP-15), glial fibrillary acidic protein (GFAP), estrogen receptor (ER), and progesterone receptor (PR). True positive staining was defined as CK7 in lung or breast; CK20 in gastrointestinal; and GCDFP-15, ER, and PR in breast carcinomas. CK7 immunoreactivity was present in all 27 lung carcinomas and 14 of 15 breast carcinomas with a sensitivity of 98% and specificity of 78%. CK20 stained 15 of 16 GI carcinomas with a sensitivity and specificity of 94%. None of the cytokeratins stained surrounding brain tissue. GCDFP-15, ER, and PR had sensitivities of 33%, 33%, and 87%, with specificities of 92%, 84%, and 28%, respectively. PR often stained nuclei of normal brain tissue and was accentuated in areas of necrosis or cautery artifact. CK7 and CK20 are highly sensitive and specific in patients with metastatic adenocarcinoma to the brain of unknown primary. GCDFP-15 and ER are relatively specific, but insensitive markers, and PR is nonspecific and difficult to interpret.