Epidermal growth factor receptor (EGFR), transforming growth factor alpha (TGFA), and p53 are frequently overexpressed in squamous cell carcinomas (SCC) of the upper aerodigestive tract. We chose to study SCC of the tongue base, which is often advanced at presentation and fatal, to evaluate whether overexpression correlates with survival. Complete follow-up was available for 20 patients, 18 of whom had stage III or IV disease. A number of clinical (age, sex, stage of disease) and histologic (tumor grade, keratinization, mitotic rate, perineural invasion, lymphatic invasion, vascular invasion, host response) variables were analyzed. None of these variables correlated with survival. Immunohistochemical analysis was performed on paraffin-embedded tissue from each patient. Because EGFR and TGFA expression were routinely found in normal squamous epithelium, overexpression was considered present if greater uptake of the antibody was manifested by a deeper immunostain. In contrast, p53 oncoprotein was not detected in normal epithelium, so detection of the antibody was believed to indicate overexpression. EGFR was overexpressed in 60% of tumors, TGFA in 35%, and p53 in 20%. Those patients who had an overexpression of p53 had a greater mean survival than those who did not (48 versus 16 months, respectively, p = 0.06). This difference was significant for patients with clinical stage IV lesions (p = 0.03). EGFR overexpression and TGFA overexpression did not correlate with survival. p53 may serve as a biologic marker indicative of improved survival potential.