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Since the 1970s, Americans’ overall mistrust in medicine has risen steadily, but limited work has been done in examining the contributions of population aging and cohort succession in driving this phenomenon. To dissect societal trends in mistrust in medicine, I use 47 years of nationally representative survey data and apply age-period-cohort interaction models, which are theoretically grounded in the sociological conception of cohort as the statistical and experiential interaction of belonging to a particular age group at a particular time period. Findings from this study add three novel contributions to the sociological literature. First, I provide empirical evidence of medical mistrust operating as a life course process both historically and currently. In particular, I find that mistrust in medicine generally increases as individuals age, but more quickly in cohorts entering adulthood after 2000. Second, my findings suggest that medical mistrust as an increasing sociological phenomenon is distinct from declining trust in other institutions, including science and business, and general trust in other people. Finally, the substantial increases across all ages and cohorts in the years post-2000 (period effects) are not explained by use of the internet, changes in population-level educational attainment, political affiliation, or self-health.