Improving the effectiveness of antidrug ads is an important public health concern. Central to achieving this aim is identifying the message strategies that address the differential characteristics of adolescent audiences. This study examined the effects of gain versus loss frame antidrug ads on adolescents with different social and behavioral characteristics. A posttest-only experiment was conducted to examine if these audience factors moderate the effects of message framing. Loss-frame messages, rather than gain-frame messages, were more persuasive for adolescents who report that their friends use drugs. Neither gain nor loss framing had a persuasive advantage for adolescents who report that their friends do not use drugs, although this outcome may be the result of a ceiling effect. Implications of the results for future theory and research are discussed.