Although rates of cigarette smoking have declined in the US, many individuals report experiencing significant barriers to quitting smoking, including poor mental health. Two prominent affective vulnerability factors that independently underlie both smoking behavior and processes and mental health include distress tolerance and anxiety sensitivity. However, limited work has examined the concurrent role of these factors on motivational reasons for smoking. The current study is a secondary analysis of baseline data from a nationally recruited sample of individuals (N = 156; Mage = 29.74, SD = 7.72; 69.2% female) interested in participating in a digitally delivered intervention for comorbid smoking and low distress tolerance. Two-step hierarchical linear regression was used to examine the unique role of self-reported distress tolerance and anxiety sensitivity in relation to reasons for smoking (i.e., habitual, negative affect reduction, addictive, pleasurable/relaxation, stimulation, and sensorimotor manipulation). Results indicated that lower levels of distress tolerance and greater levels of anxiety sensitivity were associated with greater sensorimotor manipulation reasons for smoking. Only distress tolerance was related to addictive, negative affect reduction, and stimulation reasons for smoking, whereas only anxiety sensitivity was related to habitual reasons for smoking. The current findings suggest that there is an explanatory utility for unique and multi-risk effects for distress tolerance and anxiety sensitivity for understanding smoking motives.