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Background: The proto-oncogene eIF4E has been found to be elevated in head and neck squamous cell carcinomas. In an earlier prospective study overexpression of eIF4E, detected by Western blot analysis, in histologically normal surgical margins correlated with an increased local-regional recurrence rate during a 1-year follow-up., Objective: To test the reverse hypothesis that absence of overexpression of eIF4E in the surgical margins is a predictor for long-term survival in patients with squamous cell carcinoma of the head and neck., Design: A retrospective analysis was performed on 31 patients who underwent surgery for squamous cell carcinoma of the larynx or hypopharynx. Immunohistochemical analysis was used to detect eIF4E on paraffin embedded sections of the tumor and the histologically negative surgical margins., Results: All 31 patients overexpressed eIF4E in the tumors. Thirteen patients had no detectable level of eIF4E in the margins, and only 1 had a local-regional recurrence. The average disease-free interval in this group of patients was 82.08 months. The remaining 18 patients all overexpressed eIF4E in the surgical margins (eIF4E score range, 5-80). Twelve (67%) of these patients developed a recurrence; the average disease-free interval was 31.95 months. Cox regression analysis showed that eIF4E in the margin (P= .01), nodes (P= .06), site (P= .02), and age (P= .02) had significant effects on the disease-free interval. The Kaplan-Meier survival curves were significantly different for eIF4E-positive and eIF4E-negative margins (P = .002)., Conclusions: eIF4E in the surgical margins is an independent prognostic factor and its absence in surgical margins may predict long-term survival. Detecting eIF4E in the margins may improve survival by determining which patients would benefit from further resection or adjuvant therapy.