This research examines the influence of cultural worldviews and message framing on public opinions toward the human papillomavirus (HPV) vaccination mandate. Consistent with the cultural theory of risk, we found that individuals with a hierarchical (vs. egalitarian) worldview perceived the HPV vaccination mandate as less beneficial and riskier. The hierarchy-egalitarianism dimension of cultural worldview also interacted with message framing to influence support for the mandate. For individuals with a hierarchical worldview, a loss-framed (vs. gain-framed) message resulted in greater support for the mandate and more positive thoughts, whereas the reverse was found for those with an egalitarian worldview. Results concerning the individualism-communitarianism dimension of cultural worldview showed a different pattern, however. Implications of the findings are discussed.