This study assesses attitudes towards COVID-19 vaccination and the predictive value of COVID-VAC, a novel scale, among adults in the four largest US metropolitan areas and nationally. A 36-item survey of 6037 Americans was conducted in mid-April 2021. The study reports factors for COVID-19 vaccine acceptance among: (1) already vaccinated; (2) unvaccinated but willing to accept a vaccine; and (3) unvaccinated and unwilling to vaccinate. More than 20% were unwilling to vaccinate, expressing concerns about vaccine efficacy and safety and questioning the disease's severity. Poverty, working outside of the home and conservative political views are predictors of unwillingness. Conversely, those who either personally tested positive for COVID-19, or had a family member who did so, were more likely to accept vaccination. Majorities of all respondents supported vaccination mandates for employees and university students. Respondents preferred to receive vaccines in their doctor ' s office. Lower income and conservative ideology, but not race, were strongly associated with vaccine unwillingness. The predictive value of COVID-VAC was demonstrated. While vaccination mandates are likely to be accepted, additional effective, targeted interventions to increase vaccine uptake are needed urgently.