IMPORTANCE The US veteran population represents a unique cohort of patients in whom human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has yet to be investigated. OBJECTIVE To investigate the incidence and characteristics of HPV-positive HNSCC within the veteran population. DESIGN, SETTING, AND PARTICIPANTS Retrospective medical record review including patients with HNSCC diagnosed between January 1, 2010, and November 15, 2013, from the VA Greater Los Angeles Healthcare System. Data were collected between November 16, 2013, and June 19, 2014, and analyzed between June 20, 2014, and March 26, 2015. EXPOSURES Chemoradiation therapy, radiation therapy, surgery, or no treatment. MAIN OUTCOMES AND MEASURES We determined HPV positivity by p16 testing. Demographic and clinicopathologic information and overall survival were extracted from medical records. RESULTS We identified 150 patients with the diagnosis of HNSCC. Sixty-nine patients had HPV-positive tumors (46%), and 65 (43%) had HPV-negative tumors (16 did not have HPV testing). Age at diagnosis ranged from 44 to 94 years (mean, 64.6 [SD, 8.0] years), and median (interquartile range) follow-up was 16.7 (8.7-27.3) years. Tumor location differed significantly between the 2 groups, with an HPV-positive predominance in the oropharynx (43 of 57 [75%]; P <.001). The HPV-positive patients were more likely to be treated primarily with combined chemoradiation therapy than radiation therapy or surgery (P <.001). T4 tumors had a nearly 9 times greater rate of mortality compared with T1 tumors (HR, 8.52 [95% CI, 2.60-18.40; P <.001); N3 disease was associated with 7.18 times greater mortality (HR, 7.18 [95% CI, 1.99-12.26]; P <.001) compared with N1 disease; and M1 disease was associated with 6.0 times greater mortality (HR, 5.99 [95% CI, 2.59-13.81]; P <.001). There were 42 total deaths during follow-up, 25 in the HPV-negative group and 17 in the HPV-positive group, with a nonsignificantly higher overall survival among HPV-positive patients independent of alcohol or tobacco use history (P =.09). CONCLUSIONS AND RELEVANCE Previous studies have found that the proportion of HPV-positive HNSCC in the general population ranges between 20% and 75%. Although the incidence of HPV-positive HNSCC in the Veterans Affairs population is comparable, these patients have unique risk factors and demographic characteristics that may suggest different prognostic factors for HPV-positive HNSCC in this population. Nonetheless, HPV-positive tumors still seem to portend a better overall prognosis regardless of alcohol or tobacco history among the Veterans Affairs population.