The risk of developing a second primary cancer is increased in patients with breast cancer, and the lung is one of the major sites involved. Moreover, the lung is the major metastatic site for breast cancers. A distinction between metastatic breast cancer and primary lung cancer can be histologically difficult, and both show an overlapping CK7+/CK20- immunoprofile in a majority of cases. The degree of difficulty increases with poorly differentiated tumors. We investigated differential expressions of TTF-1, Napsin A, surfactant apoprotein A, estrogen receptor, GATA-3, mammaglobin, and GCDFP-15 immunostains in 197 pulmonary carcinomas (158 adenocarcinomas, 39 squamous) and 115 invasive mammary carcinomas (91 ductal, 24 lobular type). In mammary carcinomas, estrogen receptor, GATA-3, mammaglobin, and GCDFP-15 were expressed in 74, 72, 64, and 62%, respectively, whereas TTF-1, Napsin A, and surfactant apoprotein A were all negative. The expressions were diffuse in estrogen receptor and GATA-3, and variable in mammaglobin and GCDFP-15. For a combination of estrogen receptor/mammaglobin or GATA-3/mammaglobin, 83% of mammary carcinomas were positive, and the detection rate was not improved by using all three markers. All lung squamous cell carcinomas were negative for all markers studied. TTF-1, Napsin A, and surfactant apoprotein A were positive in 80, 77, and 45% of pulmonary adenocarcinomas. None of the TTF-1-negative tumors expressed surfactant apoprotein A. GCDFP-15 was focally expressed in 2.5% of pulmonary adenocarcinomas, and estrogen receptor was focally expressed in one case (1.2%) of pulmonary adenocarcinoma. When metastasis from breast cancer is suspected in the lung, a combination of either estrogen receptor/mammaglobin or GATA-3/mammaglobin as breast markers, and a combination of TTF-1 and Napsin A as lung markers may be helpful for differentiating between the two. Caution should be taken in the interpretation of GCDFP-15 due to its occasional expression in pulmonary adenocarcinomas.