Little is known about the signaling pathways that contribute to treatment response in advanced stage head and neck tumors. Increased expression of epidermal growth factor receptor (EGFR) and downstream pathways such as nuclear factor kappa B (NFκB) are implicated in aggressive tumor phenotypes and limited response to therapy. This study explored the rationale for combining the proteasome inhibitor bortezomib with the EGFR inhibitor gefitinib in a subset of head and neck squamous cell carcinomas with high EGFR gene amplification. Drug responses of gefitinib and bortezomib as single agents and in combination within head and neck squamous cell carcinoma cell lines were analyzed using MTS assays. The effects of gefitinib on the activation of EGFR and itsthree major downstream pathways, Akt, STAT3 and MAPK were determined by western blotting. The activation status of NFκB and the effects of bortezomib on the canonical pathway were assessed by DNA binding assays. Resistance to lower doses of gefitinib was associated with elevated EGFR and activated Akt expression. Gefitinib was able to effectively inhibit activation of STAT3, Akt and MAPK in HNSCC to varying degrees depending on EGFR expression status. Bortezomib treatment inhibited TNFα –induced nuclear NFκB/RelA expression but demonstrated variability in levels of baseline nuclear NFκB/RelA expression between sensitive and resistant cell lines. Bortezomib effectively suppresses NFκB/RelA nuclear activation but demonstrates additional modes of cellular toxicity beyond the NFκB pathway in sensitive cell lines. Further understanding of tumor response to the targeted inhibitors gefitinib and bortezomib may provide novel approaches in managing HNSCCs.