Objective: Recent guidelines indicate adults 27–45 years old can receive the human papillomavirus (HPV) vaccine based on a shared-decision with their healthcare provider. With this expansion in recommendations, there is a need to examine the awareness and knowledge of HPV and HPV vaccination among this age group for cancer prevention. Methods: HINTS-5 Cycle-2 is a national survey of US adults, and was restricted to a complete case analysis of adults ages 27–45 years (N = 725). Sociodemographic, healthcare, and health information correlates were assessed for the outcomes of HPV awareness, HPV vaccine awareness, knowledge of HPV and cervical cancer, and knowledge of HPV and non-cervical cancers. Survey-weighted logistic regression models were conducted. Results: Most respondents were aware of HPV (72.9%) and HPV vaccination (67.1%). Respondents were more likely to be aware of HPV and HPV vaccination if they were female, had a higher level of education, and had previous cancer information seeking behaviors. Although there was widespread knowledge of HPV as a cause of cervical cancer (79.6%), knowledge of HPV as a cause of non-cervical cancers was reported by a minority of respondents (36.1%). College education was positively associated with cervical cancer knowledge (aOR = 4.62; 95%CI: 1.81–11.78); however, no significant correlates were identified for non-cervical HPV associated cancer knowledge. Conclusion: While more than half of adults ages 27–45 years are aware of HPV and HPV vaccination, there are opportunities to improve awareness and knowledge, particularly related to non-cervical cancers, as these are critical first steps toward shared decision-making for HPV vaccination in mid-adulthood.