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This study investigates how trust shapes individuals’ perceptions regarding the effectiveness of the human papillomavirus (HPV) vaccine. Using data collected from a nationally representative sample of American adults, analyses were conducted to assess the potential influence of trust in government health agencies and trust in doctors on vaccine perceptions, as well as the interactive effect of physician trust and physician communication. In line with theory, trust served as a mental shortcut leading to positive judgments about vaccine effectiveness, whereas the lack of trust functioned as a heuristic for making negative judgments. Trust also interacted with physician communication – for individuals with relatively low trust in doctors, having talked with a healthcare provider about the HPV vaccine lessened perceived vaccine effectiveness. The implications of these findings for future research and for developing health communication strategies are subsequently discussed.