Oral cancer is one of the most common types of human cancer in the world. Although the risk factors for oral cancer are well-recognized in different countries, the molecular mechanism responsible for this malignancy remains elusive particularly in the countries where betel quid chewing is prevalent. The cDNA microarray analysis was used to analyse the mRNA expression patterns of 1177 genes in ten oral cancer patients with betel quid chewing history. Eighty-four genes involving cell adhesion, cell shape, growth, apoptosis, angiogenesis, metastasis, and metabolism were deregulated. Although the expression profile of these genes was shared by certain clinical patients, there was no significant association of the expression profile with clinical staging. Functional implication of four validated genes including caspase-1, STAT-1, COX-2 and pleiotrophin was discussed. This study provides pilot data for understanding the pathogenesis of oral cancer in countries like Taiwan where betel quid chewing is prevalent.