Previous findings from a smoking cessation trial showed that smokers with a history of major depression had lower success rates than smokers without a depression history. In an attempt to explain the worse outcome observed for smokers with a history of depression, postcessation data obtained from subjects randomly assigned to the placebo condition were examined further. It was observed that in the first week of a behaviorally oriented treatment program, the frequency and intensity of psychological symptoms, particularly depressive mood, were higher among smokers with past depression, and that this discomfort was related to treatment outcome. Interventions designed to prevent dysphoric symptoms during the acute withdrawal period may improve smoking cessation outcome for smokers with a history of major depression.