Determining the primary site of a cerebral metastatic adenocarcinoma is complicated by the histologic similarity of most adenocarcinomas. Thyroid Transcription Factor-1 (TTF-1) is a highly specific marker of peripheral airway cell neoplasms. Formalin fixed tissue from 30 patients with brain metastasis whose primary sources were clinically and histologically known with certainty were analyzed for immunoreactivity to TTF-1. There were 18 cases of metastatic lung adenocarcinoma. Other metastases were from breast (6), colon (1), prostate (1), kidney (1), paranasal sinus (1), melanoma (1), and intestinal carcinoid (1). No patients with carcinoma of the thyroid were found. Positivity was regarded as intense nuclear reactivity. Twelve (67%) metastatic lung adenocarcinomas stained for TTF-1. None of the cerebral metastases from other body sites showed positivity. In addition, normal brain tissue and astrocytic tumors did not stain for TTF-1. These data show that TTF-1 is a highly specific and reasonably sensitive marker for peripheral airway cell metastasis to the brain.