Background. Rural residents of the United States have higher HPV-related cancer incidence and mortality, and suboptimal HPV vaccine uptake compared to urban residents. Purpose. We assessed differences in knowledge and awareness of HPV, HPV vaccine, and HPV-related cancers among rural and urban residents. Methods. We analyzed data from the Health Information National Trends Survey 2013 – 2014 on 6862 respondents ages >18 years. Multivariable logistic regression analyses compared urban/rural differences in knowledge and awareness of HPV, related cancers, and HPV vaccine. Models were adjusted for sex, age, race/ethnicity, education, household income, census region, health insurance, regular provider, internet use, and personal history of cancer. Results. Overall, 68.0% and 67.2% of urban residents were aware of HPV and HPV vaccine, respectively, compared to only 56.2% and 60.4% of rural residents. Adjusted models illustrated that compared to urban residents, rural residents were less likely to be aware of HPV (OR = 0.66, 95% CI = 0.50 – 0.87) and HPV vaccine (OR = 0.75, 95% CI = 0.60 – 0.93). Among those who were aware of HPV, rural residents were less likely to know that HPV causes cervical cancer (OR = 0.63, 95%CI = 0.43 – 0.94) compared to urban residents. No statistically significant differences between rural and urban residents were noted for knowledge that HPV is transmitted sexually and that it causes oral, anal, and penile cancers. Conclusion. This study highlights significant rural health disparities in knowledge and awareness of HPV and HPV vaccine. These findings mandate targeted interventions to increase awareness and seal the gap.