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The authors evaluated the efficacy of a brief image-based prevention intervention and assessed current drug use as a moderator of intervention effects. In a clinical trial, 416 high school-age adolescents were randomized to either the brief intervention or usual care control, with data collected at baseline and 3-month follow-up. The brief intervention consisted of a tailored in-person communication and a series of parent/guardian print materials based on the behavior–image model. Health behavior goal setting increased for participants receiving the brief intervention, with an effect size in the small range (d = 0.33). Overall effect sizes for cigarette smoking frequency and quantity and alcohol use frequency and quantity were small (ds = 0.16–0.21) and in favor of the brief intervention. However, adolescents reporting current substance use who received the brief intervention reduced their frequency and heavy use of alcohol, frequency and quantity of cigarette smoking, and reported fewer alcohol/drug problems, with larger effects ranging from small to approaching medium in size (ds = 0.32–0.43, ps < .01). This study suggests that brief image-based messages may increase health behavior goal setting and reduce substance use, particularly among drug-using older adolescents.