To date, there are no objective parameters regarding the early prediction of malignant transformation in leukoplakia. Expression analysis of melanoma-associated antigens (MAGE-A) can differentiate between healthy and already malignant transformed tissues. Thus, expression analysis may also be used as an additional diagnostic tool for oral pre-malignant lesions to monitor potential malignant changes. In this study, four specimens collected from the same patient within a year were examined. Specimens were taken from the part of the lesion that displayed a rapid progression from fibroma to oral squamous cell carcinoma (OSCC). Clinically and histopathologically, the oral lesion was first diagnosed as fibroma with inflammatory infiltration, then as leukoplakia with hyperplasia, then as leukoplakia with severe dysplasia, and lastly as OSCC. Expression of MAGE-A1, -A3, -A4, -A6, -A10 and -A12 was investigated in the frozen tissue specimens using RT-PCR and quantitative real-time RT-PCR. There was no expression of MAGE-A in the specimen of fibroma with inflammatory infiltration. However, four genes were expressed by the second specimen of leukoplakia with hyperplasia. With the exception of MAGE-A1, all antigens were expressed in the specimens, which were histopathologically diagnosed as leukoplakia with severe dysplasia and OSCC. Expression analysis of six different MAGE-A genes indicated a high potential for malignant change in the specimens diagnosed as leukoplakia that eventually developed into OSCC. Thus, analysis of MAGE-A expression can predict malignant transformation in leukoplakia.