To compare prevalence and predictors of knowledge that human papillomavirus (HPV) can cause oropharyngeal cancer (OPC) and cervical cancer among U.S. adults. Cross-sectional. Using Health Information National Trends Survey-5 cycles 1-4 (2017-2020), we estimated weighted prevalence of knowledge that HPV can cause OPC and cervical cancer, overall and by sex. Predictors were identified using logistic regression adjusting for age, sex, race and ethnicity, and education. Females vs. males had greater OPC knowledge (22.3 % vs. 17.1 %) [adjusted odds ratio (aOR) = 1.4; 95 % confidence interval (95 % CI) = 1.2-1.6] and cervical cancer knowledge (59.4 % vs. 40.0 %) (aOR = 2.6; 95 % CI = 2.2-3.0). Females with notably greater OPC knowledge were White vs. Black (aOR = 2.0; 95 % CI = 1.5-2.7), and had a college degree or higher vs. high school or less (aOR = 2.8; 95 % CI = 2.1-3.7). Males with greater OPC knowledge had a college degree or higher vs. high school or less (aOR = 3.1; 95 % CI = 2.2-4.4) and visited a provider 1-2 times within the past year (aOR = 1.7; 95 % CI = 1.1-2.6). Females with greater cervical cancer knowledge were White vs. Black (aOR = 2.1; 95 % CI = 1.6-2.6), had a college degree or higher vs. high school or less (aOR = 5.6; 95 % CI = 4.5-6.9), and visited a provider within the past year (aOR = 2.2; 95 % CI = 1.7-2.9). Males with greater cervical cancer knowledge were White vs. Black (aOR = 1.6; 95 % CI = 1.1-2.4), had at least $75,000 vs. $34,999 or less annual income (aOR = 1.8; 95 % CI = 1.3-2.4), had a college degree or higher vs. high school or less (aOR = 4.7; 95 % CI = 3.5-6.2), and visited a provider within the past year (aOR = 1.5; 95 % CI = 1.1-2.2). HPV-related cancer knowledge is limited, especially for OPC. Knowledge disparities exist across many social and healthcare engagement factors, emphasizing need for broader dissemination of HPV education.