Background: Human papillomavirus status is known to be prognostic for patients with HNSCC. Current data suggests that HPV-positive HNSCC tumors exhibit increased infiltration of immune cells and higher levels of T-cell exhaustion markers compared with HPV-negative tumors, possibly suggesting a difference in response patterns to immunotherapy. We evaluated whether HPV status is associated with duration of response in patients receiving anti-PD-1 inhibitors. Methods: We performed a retrospective chart review of 54 patients at Moffitt Cancer Center who received either pembrolizumab (N = 32) or nivolumab (N = 22) from February 2016 to July 2018 for R/M HNSCC. We collected the following data for our patient population: primary site of disease, stage, smoking status, duration of treatment, and overall survival (OS). Overall survival time was defined as the date of starting anti-PD-1 inhibitors to death. Primary disease site was oropharynx (N = 25), oral cavity (N = 13), larynx (N = 11), nasopharynx (N = 3) and unknown primary (N = 2). HPV status was available for 37 patients. Analysis of survival and time on treatment was done using log-rank test. Results: Overall survival was not different with respect to primary site of disease, smoking, ECOG status, or type of anti-PD-1 inhibitor, but was significantly longer for patients with HPV-positive vs HPV-negative HNSCCs (17 months vs 4.5 months; log rank p < 0.001). Time on anti-PD-1 inhibitor was also significantly longer for patients with HPV-positive HNSCCs (7 months vs 3 months; log rank p < 0.001). Conclusions: Our data suggests patients with HPV-positive R/M HNSCCs have longer duration of response and OS on anti-PD-1 inhibitors compared to HPV-negative patients.