Marijuana use is associated with anxiety, particularly among those anxiety conditions in which panic is common. It may therefore be that risk factors for panic increase the likelihood that marijuana users will experience problematic anxiety symptoms. The current study investigated the role of one such risk factor, anxiety sensitivity (AS), or the extent to which an individual is frightened of anxiety symptoms. We examined whether AS interacts with frequency of marijuana use to increase anxious responding (using a three-minute voluntary hyperventilation procedure). The sample consisted of 153 adolescents (46.4% female) ages 11-17 (M=14.92, S.D.=1.49). As predicted, AS moderated the link between lifetime marijuana use frequency and both post-challenge physiological anxiety (as indexed by skin conductance) and post-challenge subjective anxiety in female (but not male) adolescents such that those with high AS and more frequent marijuana use demonstrated the highest level of challenge-induced fear response. This effect remained even after controlling for relevant variables (e.g., age, trait anxiety, lifetime alcohol and cigarette use). Present findings suggest AS appears to serve as an important and potentially specific anxiety-related variable that deserves serious attention as a potential vulnerability factor among frequent marijuana-using females.