This study reviews available methodologies for evaluating human papillomavirus (HPV) status, as well as current evidence involving the prognostic and potential predictive value of p16 and HPV status in patients with locoregionally advanced or recurrent and/or metastatic squamous cell carcinoma of the head and neck treated with cetuximab combination regimens, with an emphasis placed on recent subgroup analyses of the phase III IMCL-9815 and EXTREME trials. Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide. It has recently been appreciated that human papillomavirus (HPV) status (or p16 status, which is a frequently used surrogate for HPV status) is prognostic for oropharyngeal SCCHN. Here, we review and contextualize existing p16 and HPV data, focusing on the cetuximab registration trials in previously untreated, locoregionally advanced, nonmetastatic SCCHN (LA SCCHN) and in recurrent and/or metastatic SCCHN (R/M SCCHN): the IMCL-9815 and EXTREME clinical trials, respectively. Taken together, the available data suggest that, while p16 and HPV are prognostic biomarkers in patients with LA SCCHN and R/M SCCHN, it could not be shown that they are predictive for the outcomes of the described cetuximab-containing trial regimens. Consequently, although HPV status provides prognostic information, it is not shown to predict therapy response, and so is not helpful for assigning first-line therapy in patients with SCCHN. In addition, we discuss assays currently used to assess p16 and HPV status, as well as the differentiation between these two biomarkers. Ultimately, we believe HPV E6/E7 polymerase chain reaction-based mRNA testing may represent the most informative technique for assessing HPV status in patients with SCCHN. While p16 is a valid surrogate for HPV status in oropharyngeal carcinoma (OPC), there is a higher risk of discordance between p16 and HPV status in non-OPC SCCHN. Collectively, these discussions hold key implications for the clinical management of SCCHN. Human papillomavirus (HPV) status (or its commonly utilized surrogate p16) is a known prognostic biomarker in oropharyngeal squamous-cell carcinoma of the head and neck (SCCHN). We evaluated implications of the available evidence, including cetuximab registration trials in previously untreated locoregionally advanced (LA) SCCHN and recurrent and/or metastatic (R/M) SCCHN. We conclude that, although p16 and HPV are prognostic biomarkers for both LA and R/M SCCHN, they have not been shown to be predictive of response to the described cetuximab-containing regimens for either indication. Thus, current evidence suggests that benefits of cetuximab are observed in both p16-/HPV-positive and -negative SCCHN.