Fatty acid synthase (FAS) is the enzyme responsible for the endogenous synthesis of saturated long-chain fatty acids from the precursors acetyl-CoA and malonyl-CoA. A growing body of evidence indicates that FAS is over expressed in several human cancers, such as prostate, breast, bladder, liver, lung, melanoma and oral squamous cell carcinoma (SCC). In the present study we used human oral SCC cell lines (SCC-4, -9, -15 and -25) as a model to investigate the role of FAS in the pathogenesis of oral cancer. RT-PCR and western blot experiments demonstrated that FAS is differentially expressed by the four oral SCC cell lines, with the highest production in SCC-9 followed by SCC-25. FAS expression in SCC-4 and -15 was similarly lower than the other cell lines. Proliferation curves and immunocytochemistry for PCNA and Ki-67 demonstrated that SCC-25 has the highest proliferative potential. In addition, the specific inhibitor of FAS activity cerulenin was able to significantly reduce the proliferation of oral SCC cells. Expression of androgen receptor was low in SCC-4, -9 and -15 and undetectable in SCC-25, whereas EGFR and c-erb-B2 were expressed in high amounts by the four cell lines. Immunocytochemical reactions showed that SCC-25 expresses higher levels of EGF compared to the other three cell lines. Finally, oral SCC cells exposed to nanomolar concentrations of exogenous EGF presented a reduction in the FAS protein levels concomitant with a decrease in their proliferation rates. Taken together, our results indicate that FAS is expressed in an apparently androgen-independent fashion in oral SCC cells and it is necessary for their proliferation.