Abstract Background The prevalence of current smokeless tobacco (SLT) use in 2019 among high school students was 4.8%, and the overall rate of SLT use was higher among high school boys (7.5%) than girls (1.8%). The U.S. Food and Drug Administration (FDA) launched “The Real Cost” Smokeless media campaign in April 2016 to educate rural youth about the dangers of SLT use. In this study, we evaluate the effectiveness of “The Real Cost” Smokeless campaign. Methods We use a 3-year (Jan 2016 – Dec 2018) randomized controlled longitudinal field trial that consists of a baseline survey of boys and a parent/guardian and four follow-up surveys of the boys. The cohort includes 2200 boys who were 11 to 16 years old at baseline and lived in the rural segments of 30 media markets (15 treatment markets and 15 control). “The Real Cost” Smokeless campaign targets boys who are 12 to 17 years old in 35 media markets. It focuses primarily on graphic depictions of cosmetic and long-term health consequences of SLT use. The key outcome measures include beliefs and attitudes toward SLT that are targeted (explicitly or implicitly) by campaign messages. Results Using multivariate difference-in-difference analysis (conducted in 2019 and 2020), we found that agreement with 4 of the 11 explicit campaign-targeted belief and attitude measures increased significantly from baseline to post-campaign launch among boys 14 to 16 years old in treatment vs. control markets. Agreement did not increase for boys 11–13 years old in treatment vs. control markets and only increased for one targeted message for the overall sample. Conclusions These findings suggest that “The Real Cost” Smokeless campaign influenced beliefs and attitudes among older boys in campaign markets and that a campaign focused on health consequences of tobacco use can be targeted to rural boys, influence beliefs about SLT use, and potentially prevent SLT use.