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High-risk human papillomavirus (HPV) is among the most common causes of head and neck cancer (HNC) with increasing incidence. HPV-associated HNC patients’ clinical response to treatment varies drastically, which has made treatment de-escalation clinical trials challenging. To address the need for noninvasive biomarkers that differentiate patient outcomes, serum antibodies to E7 oncoprotein levels were evaluated in serial serum specimens from HPV-positive HNC patients ( n = 48 ). We have found that increasing antibodies to E7 throughout treatment correlates with increased cancer recurrence or progression to mortality ( p = .004 ) with 100% specificity as a predictive test.