HPV positivity confers an improved prognosis in head and neck squamous cell carcinoma (HNSCC), but some of these patients recur despite radiation and chemotherapy. The first aim of this work is to identify transcriptomic and proteomic differences in HPV(+) HNSCC tumors, which are resistant to chemoradiation. The second aim is to identify upstream drivers mediating tumor HPV(+) tumor responsiveness to therapy. Elucidation of these aims would be integral in both determining HPV(+) HNSCC patient prognosis, and contributing to the development of therapeutic strategies. We utilized genomic sequencing information classifying the HPV status of patients with (HNSCC) from The Cancer Genome Atlas (TCGA) to generate two cohorts: HPV(+) patients who responded to chemoradiation (n=50), and HPV(+) patients whose disease recurred despite treatment (n=13). We utilized whole transcriptome data from these patients, and compared differences in mRNA expression using the DESeq R-package. Additionally, we used an in-house algorithm which performs iterative Kaplan Meier (KM) analysis for each gene in the transcriptome to determine which genes are the best indicators of either improved or detrimental prognosis. Pathway enrichment of statistically significant genes (p<0.05, average KM survival difference > 6 months) was performed using the EnrichR python script. Protein array data from TCGA was collected and analyzed in a similar fashion. Whole transcriptome KM analysis identified 417 genes whose expression levels were significant indicators of HPV+ tumor responsiveness to chemoradiation. Additionally, 358 genes were prognostically significant markers of HPV+ tumor recurrence. Strikingly, IFNγ signaling was both the most enriched transcriptional activator of gene markers of tumor responsiveness (p=0.006), and the most enriched transcriptional inhibitor of gene markers of tumor recurrence (p=0.008). Correspondingly, the IFNγ-induced tumor suppressor P16INK4A was the single most down-regulated protein in HPV+ tumors which recurred despite chemoradiation (p=0.02). Our data suggests that a lack of IFNγ signaling is a major driving force behind HPV(+) HNSCC resistance to therapy. Previous literature has demonstrated that IFN-γ signaling induces P16INK4A production. Additionally, P16INK4A has been previously shown to sensitize tumor cells to radiotherapy by a variety of proposed mechanisms, including its involvement in cell cycle regulation, and inhibition of DNA damage repair. While the effect of IFNγ on HPV(+) response to chemoradiation is likely multifactorial, we propose that one mechanism by which IFNγ mediates responsiveness of HPV+ HNSCC tumors is through the production of P16INK4A . Future directions include elucidating the cause of diminished IFNγ signal transduction in HPV+ recurrence, and utilizing this information for prognostic and therapeutic purposes.