Background. Fatty acid synthase (FASE) is required for fatty acid synthesis. Elevated levels of FASE have been observed in a variety of malignancies. Methods: We examined the expression of FASE in 56 primary squamous cell carcinomas (SCC) of the tongue using immunohistochemistry (IHC) with a monoclonal antibody to FASE. Results: Immunoreactivity was low in histologically normal epithelium (0.42 ± .07, n = 43), moderate in mildly dysplastic epithelium (1.41 ± 11, n = 40), and strong in SCC of the tongue (1.64 ± 10, n = 50). Both mild dysplasia and SCC stained more strongly than histologically normal epithelium (p<0.00001). Well-differentiated tumors showed increased immunoreactivity when compared to less well-differentiated tumors (p=0.044). Decreased overall survival was observed among patients with tumors with low immunoreactivity (p=0.04). Conclusions: Increased expression of FASE in dysplasia and squamous carcinomas of the oral tongue may be an indicator of both differentiation and early neoplastic change. FASE expression may be useful diagnostically, prognostically, and as a potential target for therapy.