The prognosis and disease-free survival rates for head and neck squamous cell carcinoma (HNSCC) have remained relatively stagnant for the last several decades. Moreover, as is the case with other malignancies, locoregional recurrence and distant metastasis are all too common even after seemingly successful oncologic surgery and adjuvant therapy. Recently, increased focus has been placed on understanding the influence of perioperative factors on tumor cell behavior and surgical outcomes. More specifically, emerging research suggests that anesthetic agents may play a role in cancer recurrence by interacting with prosurvival protein signaling pathways which harden tumor cells against oncologic treatments. In the present pilot study, we tested the hypothesis that inhalational anesthesia and total intravenous anesthesia (TIVA) exert differential effects on the proteomic expression of HNSCC. Ten patients with previously untreated oral cavity or oropharyngeal HNSCC were randomized to receive either sevoflurane and remifentanil or propofol and remifentanil for the duration of their respective surgeries. Morphoproteomic analysis using 10 pro-oncogenic protein markers was performed on both pre- and postanesthesia tumor samples to qualitatively grade changes in protein expression. The results of this analysis demonstrated differential expression of several protein markers. Specifically, the exposure to sevoflurane but not TIVA resulted in a statistically significant increase in the expression of cytoplasmic hypoxia-inducible factor-2alpha (P= 0.049) and nuclear p-p38 mitogenic-activated protein kinase (P= 0.041). This study represents one of the first to evaluate the effects of anesthesia on the molecular biology of HNSCC in vivo, and the results suggest that the exposure to sevoflurane may increase the expression of pro-oncogenic protein markers in HNSCC tumor cells.