Importance: Stigma toward people with opioid use disorder (OUD) is pervasive in clinical settings, impeding delivery of high-quality care. To date, no study has evaluated the effect of different stigma-reduction messages or messengers among health care professionals., Objective: To evaluate the effect of OUD-related messages delivered by different messengers on stigma and attitudes toward people with OUD among health care professionals., Design, Setting, and Participants: This randomized clinical trial examined the effects of OUD-related messages delivered by a visual campaign alone or in combination with a written narrative vignette from the perspective of 1 of 3 messengers. Health care professionals in the US were recruited from 2 national online survey panels (Ipsos KnowledgePanel and SurveyHealthcareGlobus). A total of 1842 participants completed a web-based survey measuring stigma toward people with OUD from November 13 to 30, 2020., Interventions: Eight groups were exposed to 1 of 2 message frames. One frame (Words Matter) emphasized the harm of stigmatizing language, and the other (Medication Treatment Works) focused on the effectiveness of medications approved by the US Food and Drug Administration for the treatment of OUD. Message frames were communicated through either a visual campaign alone or a visual campaign in combination with a written narrative vignette from the perspective of a simulated patient with OUD, a clinician, or a health care system administrator., Main Outcomes and Measures: Dimensions of stigma toward people with OUD were measured on 5-point Likert scales that included items about desire for social distance from people with OUD, perception of individual blame for OUD, perspective of OUD as a medical condition, and support for increased governmental spending on OUD treatment. The level of warmth felt toward people with OUD was measured by a feeling thermometer (range, 0-100 points)., Results: Among 1842 participants, the mean (SD) age was 47 (13) years; 1324 participants (71.9%) were female, 145 (7.9%) were Hispanic, 140 (7.6%) were non-Hispanic Black, 1344 (73.0%) were non-Hispanic White, and 213 (11.6%) were of other non-Hispanic race (ie, individuals who did not self-report race as Black or White and did not self-report ethnicity as Hispanic). Compared with nonexposure, exposure to the combination of visual campaign and narrative vignette communicating the importance of nonstigmatizing language from the perspective of a patient with OUD was associated with a lower probability (difference, -16.8 percentage points, 95% CI, -26.1 to -7.4; P < .001) of unwillingness to have a person with OUD marry into the family (a measure of social distance preference) and a 7.2-point (95% CI, 3.2-11.1; P < .001) higher warmth rating. Participants exposed to the combined visual campaign and patient vignette about the value of medication treatment for OUD also had significantly lower levels of stigma compared with those in the nonexposed control group (eg, unwillingness to have a person with OUD as a neighbor: difference, -15.3 percentage points; 95% CI, -24.6 to -6.0; P = .001)., Conclusions and Relevance: In this study, messages about nonstigmatizing language and effective medication for OUD reduced stigma among health care professionals. Stigma-reduction efforts targeting health care professionals may improve health care system capacity to serve people with OUD., Trial Registration: ClinicalTrials.gov Identifier: NCT05127707.