It is estimated that nearly 50,000 individuals in the United States will be diagnosed with head and neck cancer in 2017 (American Cancer Society www.cancer.org). Ninety percent of oral cancers are head and neck squamous cell carcinoma (HNSCC). Major obstacles in the treatment of HNSCC are recurrence and treatment resistance, which contributes to increased mortality. Therefore, there is increased need to determine genetic alterations in HNSCC that may be ideal novel drug targets, and biomarkers to improve diagnostic and prognostic testing. Abnormal localization and overexpression of base excision repair protein and transcriptional regulator Apurinic/Apyrimidic endonuclease (APE1) has been associated with treatment resistance and poor prognosis. Therefore, we explored mechanisms for how APE1 contributes to treatment resistance and increased mortality in HNSCC. Because oxidative stress heavily influences APE1’s expression and transcriptional regulatory activities, we examined genes involved in oxidative stress management, including SOD3 and NRF2. PPARGC1A, a NRF2 transcriptional co-activator, was also examined as our lab previously observed a link between APE1 and PPARGC1A expression. This previous work also revealed that APE1 suppressed gene expression of tumor suppressor, decorin (DCN). To examine possible mechanisms for how APE1 regulates expression of tumor suppressors and antioxidants, digital image analysis of immunohistochemistry staining was used to identify alterations in protein expression. Nuclear and total cellular protein expression of APE1, DCN, NRF2, PPARGC1A, and SOD3 were quantified in regions of proximal benign, carcinoma in situ (CIS) and invasive HNSCC. Patient survival analysis revealed that increased APE1, DCN, and PPARGC1A protein levels were significantly associated with reduced survival in CIS, benign, and invasive tissues respectively. Using multivariate analysis of protein expression, we identified that increased APE1 protein levels in the CIS of primary tumors were associated with the presence of cancer invaded lymph nodes. Elevated DCN and SOD3 protein levels in benign tissue were associated with poorly differentiated tumors as was reduced PPARGC1A in CIS. Most importantly, potential prognostic biomarkers for use in early cancer development were identified. Identifying poor prognosis in early cancer development allows the possibility of improved treatment strategies, which could prevent invasive cancer development, and increase patient survival.