While HPV-positive oropharyngeal carcinoma (OPC) patients have superior outcome relative to HPV-negative patients, the underlying mechanisms remain poorly understood. We conducted a proteomic investigation of HPV-positive (n=27) and HPV-negative (n=26) formalin-fixed paraffin-embedded OPC biopsies to acquire insights into the biological pathways that correlate with clinical behavior. Among the 2,633 proteins identified, 174 were differentially abundant. These were enriched for proteins related to cell cycle, DNA replication, apoptosis and immune response. The differential abundances of cortactin (CTTN) and methylthioadenosine phosphorylase (MTAP) were validated by immunohistochemistry in an independent cohort of 29 OPC samples (p=0.023 and p=0.009, respectively). An additional 1,124 proteins were independently corroborated by comparison to a published proteomic dataset of OPC. Furthermore, utilizing The Cancer Genome Atlas (TCGA), we conducted an integrated investigation of OPC, attributing mechanisms underlying differential protein abundance to alterations in mutation, copy number, methylation, and mRNA profiles. A key finding of this integration was the identification of elevated cortactin oncoprotein levels in HPV-negative OPCs, potentially contributing to reduced survival in these patients via its established role in radiation resistance. Through interrogation of TCGA data, we demonstrated that activation of the β1-integrin/FAK/cortactin/JNK1 signaling axis and associated differential regulation of AP-1 transcription factor target genes is a plausible consequence of elevated cortactin protein levels.