High-risk human papillomavirus (HPV) is both causative and prognostic in the majority of oropharyngeal squamous cell carcinomas (OPSCCs). The aim of this study was to evaluate for transcriptionally-active HPV in matched primary OPSCCs and their distant metastases given the implications of HPV status for diagnosis and treatment. Twenty matched pairs of primary OPSCC and their distant metastases were retrieved from departmental files. Two study pathologists reviewed all cases to confirm the diagnoses and to evaluate histologic features. Real-time PCR (RT-PCR) for detection of E6/E7 mRNA for all major high-risk HPV types and p16 immunohistochemistry were performed. Distant metastases were to lung (70 %), bone (20 %), non-regional lymph nodes (5 %) and pericardium (5 %). Histologically, 15 primary tumors were nonkeratinizing, 3 nonkeratinizing with maturation, one basaloid, and one keratinizing. Seventeen (85 %) of the metastases had the same histologic type as the primary tumor. All 20 matched pairs were concordant for HPV status by RT-PCR and for p16 expression with 19 of 20 cases positive for high risk HPV and one negative. HPV types were concordant in all cases. These findings show that the distant metastases from HPV-related primary OPSCCs uniformly retain transcriptionally-active HPV and p16 overexpression. They also retain similar morphology. This argues that HPV status can be utilized to differentiate metastatic OPSCC from separate, new, primary squamous cell carcinomas in other organs, and that therapies specifically targeting HPV or virus-related proteins in patients with distant metastases can be utilized.