AbstractClinical and experimental data suggest that ErbB‐4, a member of the epidermal growth factor receptor family, may have a role in cancer progression and response to treatment. We found recently, using a retrospective clinical analysis, that expression of ErbB‐4 receptor is correlated with metastatic potential and patient survival in non‐small‐cell lung cancer (NSCLC). The purpose of this work was to correlate the expression of the ErbB‐4 and lung cancer cells growth in vitro and in vivo and to determine the therapeutic potential of a monoclonal antibody to ErbB‐4 against lung cancer. For this aim, we ectopically expressed ErbB‐4 in a human NSCLC cell line that did not express the ErbB‐4 protein. Overexpression of ErbB‐4 produced a constitutively activated ErbB‐4 receptor. The transfected ErbB‐4 positive clones showed an increased cell proliferation in vitro and in vivo in comparison with parental ErbB‐4 negative cells and with the cells transfected by neomycin‐resistant gene. A monoclonal antibody to ErbB‐4 showed both an inhibitory effect on growth rate and an increasing apoptotic rate in the cells expressing ErbB‐4. The results of the current study provide evidence that ErbB‐4 plays a significant role in human lung cancer and may serve as a molecular target for anticancer therapy. © 2006 Wiley‐Liss, Inc.