Background:  Melanoma‐associated antigens‐A (MAGE‐A) are expressed in a variety of tumors but not in normal tissues. Thus, their detection is highly specific to cancer cells, which makes them potential targets for the diagnosis, prognosis and also immunotherapy of neoplastic diseases.Methods:  To determine the expression pattern and potential role of MAGE‐A antigens in oral squamous cell carcinoma (OSCC), expression patterns of MAGE‐A1–A6 and A12 were analyzed in 55 OSCC and 20 healthy oral mucosa using high‐sensitive reverse transcription‐nested polymerase chain reaction (RT‐nPCR).Results:  The 85.45% of tumor specimens expressed at least one of these genes. A significant correlation between the expression of MAGE‐A1–A6 and A12 and malignancy was ascertained (P = 0.0001). On the contrary, none of the normal mucosal specimens expressed one of the MAGE‐A subtypes. Antigen expression did not correlate with clinicopathological parameters, such as TNM classification, grading and clinical stage of OSCC.Conclusions:  Multiple simultaneous detection of MAGE‐A1–A6 and A12 expression has been found to be more specific and sensitive than the detection of single MAGE‐A antigen for the diagnostic and prognostic evaluation of OSCC. In addition, monitoring the expression of several MAGE‐A subtypes may determine suitable immunotherapeutic targets. Subsequently, coexpressed genes may be warranted for developing polyvalent vaccines.