Aims: To test, among US students: (1) whether perceived harmfulness of marijuana has changed over time, (2) whether perceived harmfulness of marijuana changed post-passage of state medical marijuana laws (MML) compared with pre-passage; and (3) whether perceived harmfulness of marijuana statistically mediates and/or modifies the relation between MML and marijuana use as a function of grade level. Design: Cross-sectional nationally representative surveys of US students, conducted annually, 1991â€”2014, in the Monitoring the Future study. Setting: Surveys conducted in schools in all coterminous states; 21 states passed MML between 1996 and 2014. Participants: The sample included 1â€‰134â€‰734 adolescents in 8th, 10th and 12th grades. Measurements: State passage of MML; perceived harmfulness of marijuana use (perceiving great or moderate risk to health from smoking marijuana occasionally versus slight or no risk); and marijuana use (prior 30Â days). Data were analyzed using time-varying multi-level regression modeling. Findings: The perceived harmfulness of marijuana has decreased significantly since 1991 (from an estimated 84.0% in 1991 to 53.8% in 2014, PÂ <Â 0.01) and, across time, perceived harmfulness was lower in states that passed MML odds ratio (OR)Â =Â 0.86, 95% confidence interval (CI)Â =Â 0.75â€"0.97]. In states with MML, perceived harmfulness of marijuana increased among 8th graders after MML passage (ORÂ =Â 1.21, 95% CIÂ =Â 1.08â€"1.36), while marijuana use decreased (ORÂ =Â 0.81, 95% CIÂ =Â 0.72â€"0.92). Results were null for other grades, and for all grades combined. Increases in perceived harmfulness among 8th graders after MML passage was associated with ~33% of the decrease in use. When adolescents were stratified by perceived harmfulness, use in 8th graders decreased to a greater extent among those who perceived marijuana as harmful. Conclusions: While perceived harmfulness of marijuana use appears to be decreasing nationally among adolescents in the United States, the passage of medical marijuana laws (MML) is associated with increases in perceived harmfulness among young adolescents and marijuana use has decreased among those who perceive marijuana to be harmful after passage of MML.