The modern concept of oncogenesis is based upon the interaction between factors which modulate cellular growth and differentiation, in particular oncogenes and tumor suppressor genes. The molecular events which induce laryngeal carcinogenesis are not yet known. Protoncogenes seem to be the target of the risk factors (cigarette smoking, alcohol abuse, ionizing radiations and, not least HPV-DNA) that are commonly considered related to laryngeal squamous cell carcinoma. New information on the role of alterations of oncogenes and/or their proteic products in laryngeal cancer will be useful in identifying new diagnostic and clinical therapeutical applications. The Authors investigated Epidermal Growth Factor Receptor (EGFR) expression in 103 primary laryngeal squamous cell carcinoma and 42 normal laryngeal tissue specimens in order to assess its clinical significance in primary laryngeal cancer. Significantly higher EGFR levels were found in cancer specimens compared with normal mucosa (p < 0.001). EGFR expression did not correlate with age, tumor localization, T classification, cervicallymphonode involvement or surgery, whereas in G3 tumors it was significantly higher than in G1-G2 (p < 0.05). Follow-up data were available for 74 cases: EGFR levels resulted significantly higher in patients who had a recurrence of the disease than those in recurrence-free patients (p < 0.05). The 24-month disease-free survival (DFS) was 58% for EGFR+ patients and 82% for EGFR-subjects. Multivariate analysis permitted identification of EGFR status and tumor localization as significant independent prognostic factors. Data reported here suggest that EGFR expression probably plays a role not only by regulating the growth of laryngeal cancer, but also by identifying a sub-set of laryngeal cancer patients at a higher degree of relapse risk and with an unfavorable prognosis. Furthermore, in this study p21-ras expression in 43 primary laryngeal cancers and in 7 normal laryngeal mucosa specimens was evaluated. Scattered p21 levels, expressed as optical density (O.D), were found in normal mucosa (median = 1.94) and in primary laryngeal tumours (median = 1.74). Higher p21 levels were found in neoplastic tissue than in normal laryngeal tissue (median = 2.54 vs median = 1.94; p = 0.023). The correlation between p21 ras protein and EGFR levels was also investigated. EGFR+ cases do not show any difference in p21 expression with respect to EGFR- cases (median = 1.52 O.D. vs median = 1.84). Our findings suggest that overexpression of p21 is associated with malignant phenotype in laryngeal cancer.(ABSTRACT TRUNCATED AT 400 WORDS)