With good loco-regional control, disease failure in p16-positive oropharyngeal squamous cell carcinoma (OPSCC) mainly results from distant metastasis (DM). Our objective was to characterize the patterns and clinical outcomes of DM in p16-positive OPSCC and compare these to patients with p16-negative disease.

Primary OPSCC patients who developed DM after completing surgical or non-surgical treatment were identified and p16 status was evaluated. Patterns of DM and post-DM progression-free (PFS) and disease-specific survival (DSS) were assessed.

Forty-one of the 66 (62%) patients with DM were p16-positive. DM patterns were not statistically different by p16 status. However, p16-positive patients developed DM later in their course and had longer survival. All p16-negative patients either had progression or died within 24 months of DM detection whereas the 2-year post-DM PFS in the p16-positive group was 20% (95% CI: 8–32.5%, p = 0.003). The 3-year post-DM disease-specific survival (DSS) estimate in the p16-positive patients was 16% (95% CI: 7–18%) while all p16-negative patients died within 34 months (p < 0.001). p16-negativity, loco-regional disease, and no/palliative versus curative intent treatment were all associated with reduced post-DM DSS in multivariate analysis.

The DM pattern did not differ remarkably between p16-positive and negative OPSCC patients in our practice. In p16-positive OPSCC with pulmonary oligometastatic disease, curative intent treatment and optimized locoregional control for the index primary prolonged survival.