HER-2/neu is a 185 kDa glycoprotein related to the epidermal growth factor receptor. Overexpressed in 25-30% of primary breast carcinomas, HER-2/neu is associated with a poor clinical outcome. Recently the FDA approved an antibody to HER-2/neu, trastuzumab (Herceptin), for the treatment of HER-2/neu overexpressing metastatic breast cancers. Relatively little is known about HER-2/neu status and lung cancers. We reasoned that if HER-2/neu status could be ascertained in non-small cell lung carcinomas (NSCLCs), and a clinical correlation can be established, a rationale for the use of Herceptin in this tumor type could be established. Using a FDA-approved standardized diagnostic kit, HercepTest, for detection of HER-2/neu in clinical specimens, we examined the expression of HER-2/neu in NSCLCs in archival paraffin-embedded specimens (N = 81). In normal epithelium, HER-2/neu expression was not detected in a majority of samples (74/81). HER-2/neu overexpression was detected in 27% of the tumors of different histological types including adenocarcinomas, large cell carcinomas, and squamous cell carcinomas. Poor to moderately differentiated, but not well differentiated tumors showed overexpression of HER-2/neu. The specificity of HercepTest was further increased (from 27% to 21%) when the expression in the few normal tissues was subtracted from the tumor score. HER-2/neu may offer an attractive predictive and prognostic factor for NSCLC.