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Research has shown that public preferences regarding punishment and treatment toward people who use drugs (PWUD) are shaped by individual, situational, and contextual factors. Yet, less is known about the role of perceptions of harm and blame on these preferences. This is particularly unfortunate when considering that others beyond the individual can be harmed and blamed for drug use, but the extent to which these concerns shape policy preferences or act as mediators is not known. Using a nationally representative Lucid sample (n = 844) and employing a unique survey experiment, our study investigates the mediating role of harm and blame on public preferences toward punishment and treatment toward PWUD. We find that perceptions of harm toward individuals, close friends and family, and society overall, all partially mediate the relationship between drug type and addiction status on both treatment and punishment preferences, while blame did not matter much. Research implications and future directions for research are discussed.