Thyroid transcription factor 1 (TTF-1) is currently the best immunohistochemical marker for carcinomas of lung origin. Our aim was to compare napsin A to TTF-1 for identifying pulmonary origin in metastatic adenocarcinoma and its mimics. One hundred fifty-five metastatic carcinomas (55 pulmonary, 100 nonpulmonary) were stained with monoclonal napsin A and TTF-1, and most also with polyclonal napsin A. The sensitivity of monoclonal napsin A, polyclonal napsin A, and TTF-1 for metastatic adenocarcinomas of pulmonary origin was 76%, 81%, and 82%, respectively. Two lung carcinomas were diffusely positive for monoclonal napsin A, but negative or equivocal for TTF-1. TTF-1 stained 9 of 100 nonpulmonary carcinomas (all thyroid), monoclonal napsin A stained 12 of 100 (4 sites), and polyclonal napsin A stained 27 of 91 (8 sites). Napsin A is expressed in a wider variety of metastatic nonpulmonary carcinomas than TTF-1, and the monoclonal antibody is more specific. Napsin A is a useful adjunct to TTF-1, because occasional lung adenocarcinomas are TTF-1 negative but napsin A positive.