Patients with HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are significantly different with regard to sociodemographic and behavioral characteristics that clinicians may use to assume tumor HPV status. Machine learning methods were used to evaluate the predictive value of patient characteristics and laboratory biomarkers of HPV exposure for a diagnosis of HPV16-positive HNSCC compared to in situ hybridization, the current gold-standard. Models that used a combination of demographic characteristics such as age, tobacco use, gender, and race had only moderate predictive value for tumor HPV status among all patients with HNSCC (positive predictive value [PPV]=75%, negative predictive value [NPV]=68%) or when limited to oropharynx cancer patients (PPV=55%, NPV=65%) and thus included a sizeable number of false positive and false negative predictions. Prediction was not improved by the addition of other demographic or behavioral factors (sexual behavior, income, education) or biomarkers of HPV16 exposure (L1, E6/7 antibodies or DNA in oral exfoliated cells). Patient demographic and behavioral characteristics as well as HPV biomarkers are not an accurate substitute for clinical testing of tumor HPV status.