Oral squamous cell carcinoma (OSCC) is one of the major health problems in Sri Lanka and the disease is associated with the habit of Betel Quid (BQ) chewing. Using 35k oligo microarrays, we analyzed the gene expression profile of 15 Sri Lankan patients diagnosed with OSCCs and pair-wised normal controls and correlated the findings with the clinicopathological data. Following the recording of the scanned array images and data analysis, results for selected candidate genes were verified using QRT-PCR. Upon analysis, a total of 263 genes [71 (27%) of unknown functions previously not reported in OSCCs and 192 (73%) of known functions] were found as differentially expressed between tumors and controls. For the genes with known functions, 66 (34%; such as COL4A1, MMP1, MMP3, PLAU, SPARC and KRT19) were previously reported in OSCC and for the remaining 126 (66%; such as CD47, APOL3, RRAGC, BPIL1 and AZGP1) this is the first report in OSCCs. Hierarchical clustering of the differentially expressed 263 genes grouped the samples into several clusters with the larger one being dominated by tumors of stage 3 and 4. Two cases (a verrucous SCC and an advanced SCC), did not cluster with any of the other samples. We found two main biological pathways (cell communication and integrin-mediated cell adhesion) and 5 gene ontology categories (transcription regulator activity, structural molecule activity, intracellular signaling, cytoskeleton and signal transduction) of relevance to the OSCCs examined. Results from the QRT-PCR verified the results from the microarray experiment. This study provides valuable information on gene expression profile of OSCCs of habitual users of BQ from Sri Lanka. Of particular interest were the list of genes of known and unknown functions and the two biological pathways that we suggest as candidate genes in oral cancers associated with BQ chewing in Southeast Asia, in particular Sri Lanka. The suggested candidate genes might be used as molecular biomarkers in the early detection of the alarming problem of OSCCs in Southeast Asia in association with BQ use. These findings provide valuable information that might help in the selection of possible biomarkers that can be used in early detection of the alarming problem of oral cancer in Southeast Asia.