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Bupropion is an antidepressant shown to be efficacious for smoking cessation. This study examined the short- and long-term effects of bupropion (300 mg/day for 10 weeks) versus placebo on depression symptoms among 497 smokers attempting to quit in a randomized trial of bupropion plus behavioral counseling. Depression symptoms were assessed via the Center for Epidemiological Studies Depression Scale (L. Radloff, 1977) at baseline, end of treatment, and at 6-month follow-up. Baseline nicotine dependence level was assessed with the Fagerström Test for Nicotine Dependence (T. F. Heatherton, L. T. Kozlowski, R. C. Frecker, & K. O. Fagerström, 1991). A regression model of depression symptoms demonstrated a significant interaction between nicotine dependence and treatment for the treatment phase and during follow-up. Depression symptoms did not mediate the effects of bupropion on abstinence at either time point. Highly nicotine-dependent smokers who receive bupropion are more likely to experience a decrease in depressive symptoms during active treatment but are also more likely to experience a rebound in depressive symptoms when bupropion is discontinued.