Overexpression of the epidermal growth factor receptor (EGFR) has been found to correlate with a poor prognosis for many cancers. The EGFR appears to play an important role in regulating cell growth during tumorigenesis and blockade of the EGFR/ligand interaction may be a means of inducing cell cytotoxicity, terminal differentiation, or apoptosis. In this report, we show that the growth of well-established xenografts of the human epidermoid carcinoma cell line KB could be significantly inhibited by the combination of cisplatin plus C225, a chimeric anti-EGFR monoclonal antibody, whereas the individual treatments had no effect on tumor growth. Substantive changes in the protein expression levels of the EGFR as well as several important cell cycle regulatory proteins were found in cells treated with the combination. In addition, cisplatin plus C225 inhibited the overall phosphorylation patterns including EGFR activation. These in vitro data suggest a mechanism of action for the in vivo therapeutic effects of C225 plus cisplatin.