Melanoma-associated antigen (MAGE) has been identified in a variety of types of cancer. The expression of several MAGE subgroups is correlated with poor prognosis and chemotherapeutic resistance. One target of chemotherapeutic treatment in head and neck cancer is the epidermal growth factor receptor (EGFR). The efficacy of tyrosine kinase inhibitors (TKI) in the context of melanoma-associated antigens is discussed in the present study. Five human squamous cell carcinoma cell lines were treated with the EGFR TKIs, erlotinib and gefitinib. The efficacy of these agents was measured using a crystal violet assay. Furthermore, the expression levels of MAGE-A1,-A5,-A8,-A9,-A11 and-A12 were determined by reverse transcription-quantitative polymerase chain reaction. The association between TKI efficacy and MAGE-A expression was analyzed by linear regression. The cell lines revealed inhomogeneous expression patterns for the MAGE-A subgroups. Four of the five cell lines demonstrated a good response to erlotinib and gefitinib. However, treatment with erlotinib induced better results than those of gefitinib, and revealed a concentration-dependent effect. The expression of MAGE-A5 and-A11 were significantly correlated with lower efficacy of erlotinib and gefitinib. By contrast, MAGE-A12 was associated with a superior response to these two drugs. One cell line, which expressed all investigated MAGE-A subgroups, was entirely resistant to the two TKIs. These results revealed a notable correlation between MAGE-A5 and-A11 and lower efficacy of EGFR TKIs. Pretreatment analysis of MAGE-A status may therefore aid improvement of chemoprevention using erlotinib and gefitinib in head and neck cancer.