ABSTRACT Tobacco use continues to disproportionately harm priority populations, such as smokers with mental health conditions and people from low socioeconomic status (SES) groups. The US Food and Drug Administration (FDA) is moving forward with a groundbreaking plan to reduce tobacco-related death and disease by lowering nicotine in combusted cigarettes to minimally addictive levels. To maximize the effectiveness of this potentially life-saving policy, its implementation needs to be accompanied by messages that address misperceptions about very low nicotine cigarettes (VLNCs; e.g., that VLNCs are less harmful than regular cigarettes). Past randomized clinical trials (RCTs) with VLNCs found that they are less addictive than cigarettes, reduce the number of cigarettes smoked per day, and have similar beneficial effects among priority populations as in the general population. However, past RCTs with VLNCs did not include messages about the products or policy. Emerging studies have begun to investigate messages about VLNCs, but so far they did not examine the effects of messages on behavior and were all hypothetical, with messages unaccompanied by use of the actual product. We propose to take the next step and bring together two streams of research (RCTs of VLNCs and messages about VLNCs) that have remained disparate but need to be combined to more closely resemble reduced nicotine policy implementation in the real world. We will address three specific aims: (1) Develop targeted messages about reduced nicotine in combusted tobacco products for smokers with serious psychological distress (SPD) and socioeconomically disadvantaged smokers using qualitative focus groups. (2) Test the impact of messages about VLNCs on tobacco use behaviors in an RCT with smokers with SPD, low-SES, and smokers who are neither. After 1-week baseline using normal nicotine content cigarettes, participants will be randomized into treatment (VLNCs and messages) or control (VLNCs only) condition. Participants in the treatment condition will be exposed to messages as inserts (small printed leaflets) in cigarette packs and print and video ads during weekly in-person visits. All participants will use VLNCs for 4 weeks and complete daily logs and weekly in-person visits. (3) Assess experiences with VLNCs and messages among the RCT participants in focus groups following the completion of the RCT. The results will contribute to the science that informs FDA regulatory actions around product review, product standards, and public education on nicotine.