c-erbB-3 is a new member of the Type I growth factor receptor family that includes epidermal growth-factor receptor (also called c-erbB-1) and HER-2/neu (also called c-erbB-2). Frequency and significance of c-erbB-3 overexpression in lung cancers have not been reported previously. A series of 549 cases of primary lung carcinomas were immunostained with a monoclonal anti-human c-erbB-3 antibody (Clone RTJ.1) using formalin-fixed, paraffin-embedded archival tissue. Sharp membranous staining or punctate cytoplasmic staining was interpreted as positive and scored 0 (< 5% of tumor cells), 1 (5-9%), 2 (10-49%), or 3 (> or = 50%). Medical records were reviewed for clinical data, including stage and survival. Actuarial cumulative survival analysis with the Mantel-Cox test was performed on 443 cases that had a single primary site in the lung of pure non-small cell carcinoma (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) and that also had follow-up data for more than 3 months. In all stages, squamous cell carcinoma showed the greatest rate of high c-erbB-3 positivity (score, 3) (34/119; 28.6%), followed by adenocarcinoma (41/256; 15.9%) and large cell carcinoma (7/66; 10.6%). Patients with high c-erbB-3 expression (score, 3) survived for significantly shorter times than did patients with low c-erbB-3-expression (score, 0-2) in Stages III and IV (P = 0.002), but not in Stage I or II non-small cell lung carcinomas. In conclusion, high c-erbB-3 expression in advanced non-small cell lung carcinomas might be an adverse prognostic factor. This finding suggests that c-erbB-3 might be a potential target for molecular therapy in advanced non-small cell lung carcinomas.