Recent scholarly attention has focused on explicating the nature of tobacco use among anxiety-vulnerable smokers. Anxiety sensitivity (fear of aversive internal anxiety states) is a cognitive-affective individual difference factor related to the development and maintenance of anxiety symptoms and disorders and various smoking processes. The present study examined the cross-sectional associations between anxiety sensitivity and a range of cognitive and behavioral smoking processes, and the mediating role of the tendency to respond inflexibly and with avoidance in the presence of smoking-related distress (i.e., avoidance and inflexibility to smoking AIS) in such relations. Participants (n = 466) were treatment-seeking daily tobacco smokers recruited as part of a larger tobacco cessation study. Baseline (pretreatment) data were utilized. Self-report measures were used to assess anxiety sensitivity, AIS, and 4 criterion variables: barriers to smoking cessation, quit attempt history, severity of problematic symptoms reported in past quit attempts, and mood-management smoking expectancies. Results indicated that anxiety sensitivity was indirectly related to greater barriers to cessation, greater number of prior quit attempts and greater mood-management smoking expectancies through the tendency to respond inflexibly/avoid to the presence of distressing smoking-related thoughts, feelings, and internal sensations; but not severity of problems experienced while quitting. The present findings suggest AIS may be an explanatory mechanism between anxiety sensitivity and certain smoking processes.