In tissue sections, thyroid transcription factor-1 (TTF-1) is a sensitive marker for adenocarcinomas of lung and thyroid origin. This immunohistochemical study evaluates the effectiveness of TTF-1 as a marker for pulmonary adenocarcinomas in paraffin sections of cell block preparations derived from effusion and fine-needle aspiration specimens. We evaluated 122 cell blocks including 8 primary and 39 metastatic pulmonary adenocarcinomas, 11 pulmonary neoplasms of other types, 50 specimens with nonpulmonary metastatic tumors, and 14 mesotheliomas. TTF-1 was reactive in 42 (89%) of 47 pulmonary adenocarcinomas. Only 1 of 4 pulmonary small cell/neuroendocrine tumors was TTF-1 positive, while 1 of 7 squamous cell carcinomas was weakly reactive. Of 50 metastatic tumors of nonpulmonary origin, focal weak reactivity was noted only for 1 metastatic ovarian carcinoma. All mesotheliomas were nonreactive. In cytologic preparations, TTF-1 is a highly selective marker for pulmonary adenocarcinoma and also can have a role in the distinction between pulmonary adenocarcinoma and mesothelioma.