Purpose: To determine the frequency of Her-2 overexpression in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site. Patients and Methods: Tumor specimens from 100 patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma were stained for the Her-2 protein using the Dako immunohistochemical method. Clinical and pathologic characteristics of patients with and without Her-2 overexpression were compared. Results: Staining for Her-5 overexpression was successful in 94 of 100 patients. Ten (11%) of 94 tumor specimens overexpressed Her-2. Eight of 10 overexpressors had poorly differentiated adenocarcinoma, and all overexpressors had predominant tumor location above the diaphragm, usually in the mediastinum or lungs. Conclusion: Her-5 overexpression occurs in a minority of patients with poorly differentiated carcinoma/ adenocarcinoma of unknown primary site. Because most overexpressors had poorly differentiated adenocarcinoma, further evaluation of patients with adenocarcinoma of unknown primary site is necessary to determine the frequency of Her-5 overexpression in this common subgroup. Evaluation of the efficacy of trastuzumab in Her-2 overexpressors with carcinoma of unknown primary site is indicated. J Clin Oncol 18:632-635. (C) 2000 by American Society of Clinical Oncology.