Methods Study design, power analysis, and eligibilityThis stratified randomized controlled trial was approved by the Institutional Review Board at the University of California, San Francisco. Given a two-sided alpha = .05 chi-square test adjusted for clustering within high schools with an intracluster correlation of .02, a total sample size of 40 high schools each with an average enrollment of 150 male ST users was estimated to be needed to provide 90% power to detect a significant difference AbstractIntroduction: Adolescent males in rural areas use smokeless tobacco (ST). We assessed the efficacy of a school-based nursedirected ST intervention among rural high school males.Methods: Study high schools were randomly selected from a public high school list of California rural counties. Consenting high schools were stratified by school size and randomly assigned within strata to intervention or no-intervention groups. After gaining parental consent, male students completed baseline and 1-year follow-up questionnaires. The intervention included peer-led educational sessions and an oral exam by the school nurse who also provided brief tobacco cessation counseling. We used binary generalized estimating equation (GEE) models accounting for clustering within schools to test no difference between groups after adjusting for year in high school using both completers only and multiple imputation for those lost to follow-up. Subgroup analyses assessed Baseline Factor × Group interaction in GEE models.Results: Twenty-one rural counties (72%), 41 randomly selected high schools (56%), and 4,731 male students (50%) participated with 65% retention. Nonsmoking ST users in the intervention group were significantly more likely to stop using ST at follow-up than those in the no-intervention group; there was no intervention effect among baseline ST users who also smoked. A higher percentage of baseline nonsmoking ST users reported smoking at follow-up than baseline non-ST-using smokers who reported using ST.Discussion: A school-based nurse-directed ST cessation program was efficacious among rural nonsmoking ST-using high school males. The potential program reach holds significant public health value. Baseline ST use facilitated smoking at follow-up.