Depressive disorders impose a significant mental health burden on individuals and our society. Among smokers there is a high comorbidity of depression/depressive symptoms (e.g., Glassman et al., 1998). Here the parietal EEG alpha asymmetry was used as a dimensional neuropsychological marker of depressive symptoms (i.e., the more depressed, the higher alpha power in the right vs. left parietal lobe during visuospatial tasks [Henriques & Davidson, 1997; Rabe et al, 2005]). Participants, all of whom were smokers and none of whom were clinically depressed, were randomly assigned to the Bupropion group (n = 30) or Placebo group (n = 80) in this double blind study. EEG data during the performance of a visuospatial task were collected prior to and after 14 days on bupropion or placebo capsules. It was found that bupropion significantly reduced the right parietal alpha power and parietal asymmetry whereas placebo did not. Self-reports on depressive symptoms with the Beck Depression Inventory (BDI) were also collected but they did not change after bupropion treatment, suggesting that EEG measures are more sensitive to subtle/early bupropion’s antidepressant effects. Finally the close investigation of individual differences showed that positive (vs. negative) parietal asymmetry during pretreatment predicted greater benefits from bupropion treatment. The present study sheds light on the antidepressant mechanisms of bupropion and represents a valuable addition to the paucity of research on the effects of bupropion on brain activity with EEG measures in general.