ProExC expression has been shown to perform similarly to p16 as an aid in the diagnosis of cervical dysplasia but has not been well characterized in head and neck squamous cell carcinomas (SCC). The purpose of this study is to determine whether ProExC performs similarly to p16 as a prognostic marker in oropharyngeal SCC and to evaluate the threshold of ProExC and p16 staining that correlates with survival. ProExC, p16, and human papillomavirus DNA in situ hybridization were performed on tissue microarray (TMA) cores and whole sections from 62 patients with oropharyngeal SCC. Sensitivity and specificity for high-risk HPV and correlation with overall survival (OS), cancer-specific survival (CSS), and time to distant metastasis (TDM) were calculated for ProExC and p16 at different thresholds. ProExC did not prove to be a robust marker. It showed strong correlation with OS at a 66% threshold on TMA cores, but correlation with OS was lost on whole sections. It also exhibited low sensitivity (53.7%) on TMA cores and low specificity on whole sections (65%). ProExC at a 33% threshold exhibited unacceptably low specificity and did not correlate with OS, CSS, or TDM. Sensitivity and specificity of p16 varied predictably with threshold: higher sensitivity and lower specificity with lower thresholds and vice versa for higher thresholds. p16 at a 50% threshold offers a balance between sensitivity and specificity, and correlates with OS, CSS, and TDM on whole sections; correlation with TDM is lost on TMA cores. These findings indicate that ProExC does not perform well enough to be used as a prognostic marker in oropharyngeal SCC. p16 should be used and scored as positive when at least half the tumor is strongly stained.