Determining the primary site of a brain metastasis can be difficult, particularly if there is no organ-specific tumor histology. Thyroid transcription factor-1 (TTF-1) is a marker commonly expressed in lung and thyroid carcinomas. We studied the value of TTF-1 staining to identify brain metastases from a lung primary. Forty-three consecutive patients metastatic carcinomas of the brain were reviewed from a 4 year period. Twenty-one (75%) of the 28 metastatic pulmonary carcinomas were TTF-1 positive (+), whereas only one metastatic papillary thyroid carcinoma (7%) out of 15 metastatic non-pulmonary carcinomas was TTF-1 (+). We also studied the cytokeratin profile of these tumors. However, cytokeratin profile, either alone or combined with TTF-1 staining, was not better than TTF-1 staining alone in identifying brain metastases of pulmonary origin. Overall, TTF-1 positivity is a useful indicator of pulmonary origin in brain metastases, with a very high positive predictive value (95%) and a moderate negative predictive value (67%).