Anti-smoking media directed at adolescents use many different message themes, but little evidence exists as to which is most effective. Additionally, little is known about how teens who smoke respond to anti-tobacco ads. This study examined smoking and nonsmoking adolescents' responses to three popular thematic approaches: (1) endangering others, (2) negative life circumstances, and (3) industry manipulation. Sixteen groups of high school students (total N=488) were randomly assigned in a balanced fashion to one of three anti-tobacco ad conditions or a control condition. Outcome variables included adolescents' immediate emotional and cognitive responses, and intentions to smoke. Adolescents exposed to negative life circumstances ads reported lower intentions to smoke than those exposed to control and industry manipulation ads. Additionally, adolescents' responses differed based on smoking status. Smokers liked the ads less and had fewer positive and more negative thoughts. Findings suggest a media campaign focusing on negative life circumstances can be an effective component of a tobacco control program aimed at adolescents. Mechanisms through which the negative life circumstances ads influence adolescents' intentions to smoke are discussed. Findings also suggest that smokers respond differently to anti-tobacco ads, and their responses need to be considered when developing effective anti-tobacco advertising campaigns.