introduction: Accumulating evidence has linked depressive symptoms and sex hormones to risk for relapse; however, the specific mechanisms involved in these associations remain unknown. This randomized crossover study assessed physiological response to nicotine by menstrual phase in female smokers with and without depressive symptoms following acute smoking abstinence. Methods: Females, ages 18-40 years with regular menstrual cycles, not on exogenous hormones or psychotropic medications, who reported smoking ≥5 cigarettes/day were enrolled. Participants were stratified into 2 groups: no depressive symptoms (NDS; n = 23) and depressive symptoms (DS; n = 24). After 4 days of biochemically verified smoking abstinence, participants completed 2 laboratory sessions in the follicular (F) and luteal (L) phases. Participants used nicotine nasal spray at Time 0, and blood pressure, heart rate, and serum nicotine were measured at Time -1, 5, 10, 20, 30, 45, 60, and 90 min. results: Participants (n = 47) were 29.1 ± 6.8 years old and smoked an average of 12.5 ± 5.1 cigarettes/day. The NDS group had more pronounced menstrual phase differences (F > L) in diastolic blood pressure, heart rate, and maximum concentrations of nicotine compared with the DS group (p <.05). conclusions: This study observed an interaction between sex hormones and depressive symptoms such that those without depressive symptoms had a greater menstrual phase difference in the physiological response to nicotine. These data offer additional support for the role of sex hormones in the physiological response to nicotine, which may play a role in menstrual phase effects on smoking cessation.