In some patients with a history of breast cancer who also have masses in the lung, making a clinical distinction between primary pulmonary neoplasia and pulmonary metastasis of mammary carcinoma may be impossible. To ascertain whether immunohistologic studies could contribute to resolving this problem, the authors undertook a prospective study of 30 cases showing synchronous or metachronous adenocarcinomas in these two sites. A predefined panel of antibodies--as derived from published antigenic catalogs for breast and lung cancer--was applied to each case. Tumors were interpreted as metastases if they were positive for gross cystic disease fluid protein-15, estrogen receptor protein, or S-100 protein. Conversely, primary adenocarcinomas of the lung were defined by their expression of carcinoembryonic antigen and a lack of the other three determinants. Using these criteria, 15 lesions were classified as metastatic; 11 were categorized as primary pulmonary adenocarcinomas; and 4 cases were indeterminate in origin. Responses to corresponding therapeutic protocols generally supported the validity of the immunohistologic diagnoses; 8 of 15 patients treated for metastatic breast cancer were well at least contact, as were 5 of 11 patients who received therapy for primary carcinoma of the lung. These data suggest that immunohistology plays a useful role in distinguishing mammary from pulmonary adenocarcinomas.