Importance: Human papillomavirus (HPV) infection is associated with oropharyngeal squamous cell carcinoma. International estimates suggest overall oral HPV prevalence is 7.5%, with prevalence of oral HPV types 16 and 18 being 1.6%; prior Australian estimates suggest oral HPV prevalence is 2.3%, with HPV-16 and HPV-18 being 1.3%. Objectives: To estimate the prevalence of oral HPV infection among Indigenous Australians and to report the prevalence of factors associated with high-risk HPV types (ie, HPV-16 and HPV-18) and HPV types linked with Heck disease (ie, HPV-13 and HPV-32). Design, Setting, and Participants: This cross-sectional study analyzed HPV screening results from saliva samples collected from 1011 Indigenous Australians between February 2018 and January 2019. Data were analyzed from May 2018 to May 2019. Recruitment occurred through Aboriginal Community Controlled Health Organisations in South Australia. Eligibility included identifying as Indigenous, residing in South Australia, and being aged 18 years or older. Main Outcomes and Measures: Saliva samples were collected, with microbial DNA for genotyping extracted. Sociodemographic parameters, health-related behaviors, and sexual history data were collected. Analyses were stratified by sex as well as by HPV types 13 and 32 (Heck disease) and 16 and 18 (high risk of oropharyngeal squamous cell carcinoma). Multivariable analyses were conducted to obtain adjusted odds ratios (ORs). Results: Data were obtained for 910 participants (median [interquartile range] age, 37 [27-51] years); 595 participants (65%) were female and 572 (63%) resided in nonmetropolitan locations. In all, 321 saliva samples (35.3%; 95% CI, 32.2%-38.4%) were positive for oral HPV (106 [33.7%] men; 215 [36.1%] women). The highest prevalence was found for HPV types 13 and 32 (207 [22.7%] total; 60 [19.0%] men; 147 [24.7%] women) followed by HPV types 16 and 18 (30 [3.3%] total; 9 [2.9%] men; 21 [3.5%] women). After multivariable analysis, risk factors associated with HPV types 13 and 32 included nonmetropolitan residential status (OR, 2.06; 95% CI, 1.10-3.88) and not having had a tonsillectomy (OR, 2.74; 95% CI, 1.05-7.16). Among women, having obtained a high school education or less was associated with lower odds of HPV-16 and HPV-18 infection (OR, 0.16; 95% CI, 0.03-0.97). Conclusions and Relevance: Prevalence of oral HPV infection in a large sample of Indigenous Australians was high, with one-third testing positive. The most prevalent HPV types were those associated with Heck disease. The prevalence of HPV types associated with oropharyngeal squamous cell carcinoma exceeded both Australian and international population-level estimates.