Background: Conflicting data exists about whether EGFR inhibition is more or less effective in pts with p16 positive or negative oropharynx cancer (OPC). We update results from two institutional clinical trials in pts with locoregionally advanced head and neck squamous cell carcinoma (LRA HNSCC) given chemoradiotherapy either with or without the oral EGFR inhibitor gefitinib (G), with specific attention to the subset of pts with p16-defined OPC. Methods: Between 1996-2000, 44 pts with LRA HNSCC were treated on a Cleveland Clinic IRB-approved protocol using concurrent cisplatin, fluorouracil and radiation without G (G- cohort). Between 2003-2007, 60 similar pts were treated using the same chemoradiotherapy regimen with the addition of G 250 mg daily for 2 years beginning on day 1 of radiation (G+ cohort). Available biopsy material from 64 OPC pts (23 G-, 41 G+) was retrieved and tested by immunohistochemistry for p16 (as a surrogate for human papillomavirus) positivity. Kaplan-Meier outcome projections were compared using the log-rank test. Results: With a median follow-up in excess of 7 years for all pts, survival and patterns of failure did not differ between the two trials. The 5-year overall survivals (OS) were 68% vs. 64% (p=0.73) and relapse-free survivals (RFS) 65% vs. 63% (p=0.85) in the G+ and G- cohorts respectively. OPC was more frequent in the more recently treated G+ cohort (68% vs. 53%). Excluding 14 pts for whom tumor was unavailable, OPC p16-positivity was also more frequent in the G+ cohort (74% vs. 63%). As expected, outcomes in the p16+ OPC pts were significantly better than in the p16- OPC pts including OS (66% vs. 58%, p=0.049) and RFS (69% vs. 56% p=0.027). However, in comparing the G+ and G- cohorts, the use of G did not significantly alter any survival outcome or pattern of failure in either the p16+ or p16- OPC pts. Conclusions: Although the retrospective nature of this analysis limits the strength of our conclusions, in the definitive management of LRA HNSCC, we could identify no effect of oral EGFR inhibition on any outcome. In subset analysis there was also no differential impact found in either the p16+ or p16- OPC pts. Clinical trial information: NCT00352105.