Background: In the USA, the human papillomavirus (HPV) vaccine is currently licensed for 9–26-year-old females, but licensure for women over 26 years is being considered. The aim of the current study was to investigate the association of sociodemographic and health-related factors to HPV vaccine acceptability among adult women. Methods: The current study utilised a nationally representative sample of women (n = 1323) aged 27–55 living in the USA, with an oversampling of black and Latina women. A multiple item measure of HPV vaccine acceptability across varying cost and location-of-availability (clinic only v. any local pharmacy) conditions was the main outcome measure. General linear modelling was used to analyse the association of vaccine cost, location availability, and sociodemographic and health-related variables with vaccine acceptability. Results: Vaccine cost had the strongest association with acceptability [F (2, 1249) = 832.1; P < 0.0001]; however, factors such as religiosity, political views, a history of various negative sexual health outcomes and previous flu shot receipt were also associated with acceptability. Location availability had a statistically significant but modest effect, with a slight preference shown for health clinic availability. Conclusions: Adult women had generally high levels of HPV vaccine acceptability, but were greatly influenced by cost of the vaccine. Women who had experienced negative sexual health outcomes due to HPV-specific infection rated the vaccine as more acceptable, perhaps due to distress associated with those outcomes.