Overexpression of human epidermal growth factor (EGFR) has been associated with a variety of human malignancies. The exact role of EGFR in human malignancies and its correlation with chemotherapeutiveness response has not been determined. Using a quantitative RT-PCR method, we previously studied the effects of cisplatin treatment on levels of EGFR mRNA in human papillomavirus (HPV)-positive head and neck cancer cell lines. In this report we extended these studies to HPV-negative head and neck cancer cells. We also compared the growth inhibition and 50% inhibitory concentration (IC50) of cisplatin between these cells. We found that three of four HPV-negative cell lines had 3 to 5 times higher cisplatin IC50 values as compared to two HPV-positive cell lines. EGFR mRNA levels were increased after exposure to cisplatin in the cell lines with the higher IC50 values, while EGFR levels were reduced after cisplatin exposure in the cell lines with the lower IC50 values. These results suggest that the cisplatin sensitivity of head and neck cancer cells corresponds to subsequent alteration of EGFR levels following cisplatin treatment.