To determine whether smokers with a history of depression are differentially susceptible to smoking withdrawal, depressed mood induction and/or hypothalamic–pituitary–adrenal (HPA) axis dysregulation during smoking abstinence, 24 women smokers with and without such a history were studied. During one 5-day interval, participants smoked ad libitum; during a second they abstained. On day 4, the participants were exposed to the Velten mood induction procedure (VMIP). Participants were then instructed to take 1 mg dexamethasone at 11 pm. At 4 pm on day 5, blood samples were withdrawn to determine the cortisol and ACTH response. Despite lower baseline cotinine levels, history-positive participants displayed more pronounced overall withdrawal distress than did history-negative participants, regardless of condition. The VMIP increased depression as well as negative responses on other profile of mood states subscales. Despite many overall group differences, no significant main effects for smoking condition nor interaction effects emerged. All participants evinced cortisol suppression in response to dexamethasone during both conditions, but the degree of suppression did not differ as a function of either abstinence or depression history. In history-positive smokers, however, ACTH levels trended toward overall elevation and showed almost no suppression during abstinence; thus exacerbation of HPA dysregulation in history-positive smokers during smoking abstinence cannot be ruled out. Copyright © 2004 John Wiley & Sons, Ltd.