History of depression in smokers has been associated with an inability to quit smoking and with an increased likelihood of smoking relapse. This study prospectively tracked nicotine withdrawal symptoms, symptoms of depression, and ability to quit smoking between smokers with and without a probable history of major depression who were trying to quit smoking with minimal assistance. Results indicated that prior to quitting, smokers with a history of depression smoked to reduce negative affect, in response to craving, and in social situations. Additionally, positive history smokers scored higher on the Center for Epidemiological Studies Depression Scale (CES-D) than did smokers without such a history. Following a quit attempt, positive history smokers were somewhat more likely to experience greater symptoms of nicotine withdrawal than negative history smokers. However, among the positive history smokers, depressive symptoms as measured by the CES-D increased significantly 4 weeks after trying to quit, compared to a decline among negative history smokers. Positive and negative history smokers did not significantly differ on ability to quit smoking within the 30-day follow-up period. History of depression appears to be associated with a delayed increase in symptoms of depression following a quit attempt. However, it remains to be demonstrated whether such an increase in depressive symptoms may influence later probability of relapse.