Background: Human papillomavirus (HPV) has emerged as a causative agent and positive prognostic factor for oropharyngeal (OP) head and neck squamous cell cancer (HNSCC). This prompts inquiry into whether recent improvements in HNSCC outcomes are due to therapy improvements or the increasing incidence of HPV-related HNSCC. Methods: We performed a review of all patients treated for locoregionally advanced HNSCC with chemotherapy and radiation at the University of Chicago on a series of prospective institutional trials. Patients were divided into three groups according to the time period during which they were treated. Groups one, two, and three were treated between 1993-1998, 1999-2003 and 2004-2010 respectively. Trends were compared for OP and non-OP. Results: 422 patients were identified with OP (55.7%) and non-OP (44.3%) cancers. All patients had ECOG 0-2. Median age was 57 yrs. OP overall survival (OS) improved over time with 5 yr OS of 42.3% (group 1), 72.5% (group 2), and 78.4% (group 3), p<0.001. There was a trend towards improved 5 yr OS for non-OP patients with 51.0% (group 1), 58.8% (group 2), and 66.3% (group 3), p=0.16. Similarly 5 yr progression free survival (PFS) improved for OP groups from 42.3% to 68.4% to 75.8% (p<0.001). The respective increase in non-OP was from 42.9% to 53.6% to 61.7% (p=0.094). Five year distant failure free survival (DFFS) was 42.3%, 71.1%, and 77.8% (p<0.001) for OP and 46.9%, 57.1%, and 66.0% (p=0.13) for non-OP. Trends remained statistically significant for OP groups after adjusting for baseline covariates but were diminished in the non-OP group (p=0.51, p=0.30, and p=0.38 for OS, PFS, and DFFS respectively). Conclusions: Over the past two decades, OP HNSCC outcomes (OS, PFS, DFFS) have significantly improved while non-OP HNSCC outcomes have trended toward improvement. Although our patients are not specifically stratified by HPV, it is likely that improving OP outcomes are due to the increasing incidence of HPV-related HNSCC in the OP. These data further justify trial stratification for HPV status, investigations of novel approaches for patients with carcinogen-related HNSCC, and current de-intensification approaches for HPV-related HNSCC.