Background: Incidence of human papillomavirus-positive oropharyngeal cancer (HPV-OPC) is increasing, and spouses of these patients have high anxiety about their own HPV-related cancer risk. Methods: Partner study of 149 HPV-OPC and 81 of their spouse/long-term partners. Data collection included a 30-second rinse and gargle (at diagnosis and again 1 year later for 103 cases and 46 partners), computer-assisted risk factor survey, tumor collection (cases), and visual oral examination (spouses). Oral rinse samples were tested for 36 types of HPV DNA using PGMY09/11 primers and line-blot amplification, and HPV16 copy-number using real-time PCR. Results: Cases were primarily male (89%), white non-Hispanic (92%), had performed oral sex (94%), and never-smokers (51%) with a median age of 56 years. Twelve-month survival was high among never- and ever-smoking HPV-OPC (100% vs 93%, p=0.18). The 81 spouses of HPV-OPC were primarily female (81%), white non-Hispanic (92%), never-smokers (54%), with a median age of 53 years. Spouses were significantly less likely than cases to have >10 lifetime oral sex partners (11% vs 39%, p<0.001). Prevalence of any oral HPV (65%) and oral HPV16 (52%) was high among HPV-OPC at diagnosis. Four (7.7%) of 52 HPV-OPC with HPV16 DNA detectable before therapy, had HPV16 persistently detected one year after diagnosis/therapy. Prevalence of any oral HPV DNA among partners was significantly lower than among HPV-OPC (7.3% vs 65%, p<0.001). Oral HPV prevalence was significantly higher among the 7 male partners than the 74 female partners (29% vs 5%, p=0.025). Oral HPV infections among partners included HPV16 (n=2), HPV62 (n=2), HPV 83 and 51 (1 each). Both partners with oral HPV16 infections were female and no longer had oral HPV16 detected at the one year follow-up. 64% of spouses had a visual oral exam, and no pre-cancers or cancers were identified. However, two (2.5%) enrolled spouses reported a personal history of cervical cancer, and 6 HPV-HNC cases (4.0%) reported a previous spouse who developed cervical or vaginal cancer. Conclusions: Oral HPV16 DNA is common among HPV-OPC, but not among their spouses. Spouses of HPV-OPC may have an elevated risk or history of cervical cancer.